The Impact protein is a translational regulator that ensures constant high levels of translation under amino acid starvation. It acts by interacting with Gcn1/Gcn1L1, thereby preventing activation of Gcn2 protein kinases (EIF2AK1 to 4) and subsequent down-regulation of protein synthesis. It is evolutionary conserved from eukaryotes to archaea [].
The Impact protein is a translational regulator that ensures constant high levels of translation under amino acid starvation. It acts by interacting with Gcn1/Gcn1L1, thereby preventing activation of Gcn2 protein kinases (EIF2AK1 to 4) and subsequent down-regulation of protein synthesis. It is evolutionary conserved from eukaryotes to archaea []. This entry represents Impact family members found mostly in bacteria, though there are also some archaeal sequences as well. Crystallography of the Escherichia coli protein YigZ shows a two-domain stucture, where the C-terminal domain is suggested to bind nucleic acids. The function of this proteins is unknown [].
The Impact protein is a translational regulator that ensures constant high levels of translation under amino acid starvation. It acts by interacting with Gcn1/Gcn1L1, thereby preventing activation of Gcn2 protein kinases (EIF2AK1 to 4) and subsequent down-regulation of protein synthesis. It is evolutionary conserved from eukaryotes to archaea []. This entry represents the N-terminal domain superfamily of the Impact proteins.
The Impact protein is a translational regulator that ensures constant high levels of translation under amino acid starvation. It acts by interacting with Gcn1/Gcn1L1, thereby preventing activation of Gcn2 protein kinases (EIF2AK1 to 4) and subsequent down-regulation of protein synthesis. It is evolutionary conserved from eukaryotes to archaea []. This entry represents the N-terminal domain of the Impact proteins.
This domain is known as the thumb domain. It is composed of a four helix bundle []. Reverse transcriptase converts the viral RNA genome into double-stranded viral DNA. Reverse transcriptase often occurs in a polyprotein; with integrase, ribonuclease H and/or protease, which is cleaved before the enzyme takes action. The impact of antiretroviral treatment on the first 400 amino acids of HIV reverse transcriptase is good. Little is known, however, of the antiretroviral drug impact on the C-terminal domains of Pol, which includes the thumb, connection and RNase H []. Evidence suggests that these might be well conserved domains.
This entry represents a domain found in one of the reticulocyte binding protein homologue family members or RH proteins expressed by the malaria parasite merozoite. RH proteins recognise erythrocytes and are important in virulence. This domain has been shown to exhibit selective binding to ATP and ADP. Binding of ATP or ADP induces nucleotide-dependent structural changes in the C-terminal hinge-region of NBD94 that directly impact on the ability of the RH to bind to the red blood cells [].
Trichome birefringence-like (TBL) is a plant protein family. In Arabidopsis this family includes 46 members (TBR, TBL1-45) []. The TBL family is proposed to encode wall polysaccharide specific O-acetyltransferases [, ]. They contain a TBL domain with a conserved glycine-aspartate-serine (GDS) signature, similar to the conserved motif (GDSL) found in some esterases/lipases [, ]. Members of the TBL protein family had been shown to impact pathogen resistance, freezing tolerance, and cellulose biosynthesis [].
A-kinase anchor protein 5 (AKAP5), also known as AKAP79, is a PKA anchoring protein that binds to adenylyl cyclase type 8 (AC8) and to regulate its responsiveness to store-operated Ca(2) entry (SOCE) []. The AKAP79 and AC8 interaction may occur in lipid raft domains of the plasma membrane, with palmitoylation of AKAP79 plays an important role in targeting the AKAP to the cholesterol- and sphingolipid-rich regions of the plasma membrane where it can impact on local Ca2 -stimulated AC8 activity [].
Gibberellins are plant hormones which have great impact on growth signalling. DELLA proteins are transcriptional regulators of growth related proteins that lack a DNA binding domain and exert its negative regulation of gibberellin responses through interaction with other transcription factors []. DELLAs are downregulated when gibberellins bind to their receptor GID1 [, ], which forms a complex with DELLA proteins and signals them towards 26S proteasome. The N-terminal of DELLA proteins contains conserved DELLA and TVHYNP motifs which are important for GID1 binding and proteolysis of the DELLA proteins [, ].
The CAF-1 or chromatin assembly factor-1 consists of three subunits, and this is the first, or A []. The A domain is uniquely required for the progression of S phase in mouse cells [], independent of its ability to promote histone deposition []but dependent on its ability to interact with HP1 - heterochromatin protein 1-rich heterochromatin domains next to centromeres that are crucial for chromosome segregation during mitosis. This HP1-CAF-1 interaction module functions as a built-in replication control for heterochromatin, which, like a control barrier, has an impact on S-phase progression in addition to DNA-based checkpoints [].
Gibberellins are plant hormones which have great impact on growth signalling. DELLA proteins are transcriptional regulators of growth related proteins that lack a DNA binding domain and exert its negative regulation of gibberellin responses through interaction with other transcription factors []. DELLAs are downregulated when gibberellins bind to their receptor GID1 [, ], which forms a complex with DELLA proteins and signals them towards 26S proteasome. The N-terminal of DELLA proteins contains conserved DELLA and TVHYNP motifs which are important for GID1 binding and proteolysis of the DELLA proteins [, ].
This entry describes an N-terminal domain found in Antigen I/II (also known antigen B, PAc or adhesin P1).The cariogenic bacterium Streptococcus mutans uses adhesin P1 to adhere to tooth surfaces, extracellular matrix components, and other bacteria. The N terminus forms a stabilizing scaffold by wrapping behind the base of P1's elongated stalk and physically 'locking' it into place. It is suggested that the N-terminal has a pronounced impact on P1 immunogenicity, antigenicity, folding, stability, and adherent function [].This domain can also found in aggregation substance (Asa1) from Enterococcus faecalis. It is a structural homologue of Streptococcus mutans Antigen I/II. It acts as an adhesin mediating cell-cell contact between different E. faecalis strains and also binding of E. faecalis to eukaryotic cells [, ].
The Ret finger protein-like (RFPL) protein family members includes RFPL1, RFPL2, RFPL3 and RFPL4. In humans, RFPL transcripts can be detected at the onset of neurogenesis in differentiating human embryonic stem cells, and in the developing human neocortex []. The human RFPL1, 2, 3 genes have a role in neocortex development. RFPL1 is a primate-specific target gene of Pax6, a key transcription factor for pancreas, eye and neocortex development. Human RFPL1, 2 and 3 are reported to impact on cell number, specifically through the RFPL-defining motif (RDM) and SPRY domains []. The RFPL4 (also known as RFPL4A) gene encodes a putative E3 ubiquitin-protein ligase expressed in adult germ cells and interacts with oocyte proteins of the ubiquitin-proteasome degradation pathway [].
Arl2 (Arf-like 2) GTPases are members of the Arf family that bind GDP and GTP with very low affinity. Unlike most Arf family proteins, Arl2 is not myristoylated at its N-terminal helix. The protein PDE-delta, first identified in photoreceptor rod cells, binds specifically to Arl2 and is structurally very similar to RhoGDI. Despite the high structural similarity between Arl2 and Rho proteins and between PDE-delta and RhoGDI, the interactions between the GTPases and their effectors are very different. In its GTP bound form, Arl2 interacts with the protein Binder of Arl2 (BART), and thecomplex is believed to play a role in mitochondrial adenine nucleotide transport []. In its GDP bound form, Arl2 interacts with tubulin- folding Cofactor D; this interaction is believed to play a role in regulation of microtubule dynamics that impact the cytoskeleton, cell division, and cytokinesis [].This entry also includes Alp41 from fission yeasts which is essential for the cofactor-dependent biogenesis of microtubules [].
TCF-19, also termed transcription factor SC1, was identified as a putative trans-activating factor with expression beginning at the late G1-S boundary in dividing cells []. It also functions as a novel islet factor necessary for proliferation and survival in the INS-1 beta cell line. It plays an important role in susceptibility to both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM); it has been suggested that it may positively impact beta cell mass under conditions of beta cell stress and increased insulin demand [].TCF-19 contains an N-terminal fork head association domain (FHA), a proline rich region, and a C-terminal plant homeodomain (PHD) finger. The FHA domain may serve as a nuclear signaling domain or as a phosphoprotein binding domain. The proline rich region is a common characteristic of trans-activating factors. The PHD finger may allow TCF-19 to interact with chromatin via methylated histone H3 [].
This entry represents the C-terminal region found in viral movement proteins (MP) of the 30K type. This region has been suggested to be conserved in secondary structure in Ophioviruses Mps. It contains two parts, (i) a long segment with the potential to form an α-helix (alphaB), rich in charged residues, and (ii) a region highly variable in sequence downstream of alphaB.The C-terminal region corresponds to the protease domain which contains a strictly conserved DTG tripeptide, also found in related aspartic retroviral proteases. This protease is required for autocleavage of the Movement Protein of ophioviruses in an N-terminal part that supports movement of viral particles through the plant, and this C-terminal part which retains protease activity []. contains a strictly conserved DTG tripeptide which is probably conserved for functional, rather than structural reasons. Mutations in the aspartate residue in the core domain had an impact on cell to cell movement [].
Positive-stranded RNA (+RNA) viruses that belong to the order Nidovirales infect a wide range of vertebrates (families Arteriviridae and Coronaviridae) or invertebrates (Mesoniviridae and Roniviridae). Examples of nidoviruses with high economic and societal impact are the arterivirus porcine reproductive and respiratory syndrome virus (PRRSV) and the zoonotic coronaviruses (CoVs) causing severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and Covid-19 (SARS-CoV-2) in humans. The replicase gene encodes two polyproteins, pp1a and pp1ab, which are proteolytically processed to nonstructural proteins (NSPs). Among the NSPs found in Nidovirales, nonstructural protein 15 (NSP15) from coronaviruses (CoV) and NSP11 from arteriviruses (AV) participate in the viral replication process and in the evasion of the host immune system. They contain in their C-terminal region a conserved endoribonuclease domain called nidoviral uridylate-specific endoribonuclease (NendoU) with cleavage specificity for single- and double-stranded RNA 5' of uridine nucleotides to produce a 2'-3'-cyclic phosphate end product. Arterivirus Nsp11 contains two conserved compact domains: the N-terminal domain (NTD) and C-terminal domain (NendoU), whereas CoV NSP15 folds into three domains: N-terminal, middle domain, and C-terminal catalytic NendoU domain. No counterpart corresponding to the NTD of CoV NSP15 exists in AV NSP11. The NTD of AV NSP11 is small and related to NSP15 middle domain, which may serve as an interaction hub with other proteins and RNA [, , , , , ].This domain contains a central β-sheet flanked by two small α-helices on either side [, , ].
This is the bZIP domain found in plant transcription factors with similarity to Oryza sativa RF2a and RF2b, which are important for plant development. RF2a and b interact, as homodimers or heterodimers, with each other, and activate transcription from the RTBV (rice tungro bacilliform virus) promoter, which is regulated by sequence-specific DNA-binding proteins that bind to the essential cis element BoxII. They show differences in binding affinities to BoxII, expression patterns in different rice organs, and subcellular localisation. Transgenic rice with increased RF2a and RF2b display increased resistance to rice tungro disease (RTD) with no impact on plant development [, ].bZIP domains from Arabidopsis have been classified into 11 groups (groups A-I and S), the ones included in this entry belong to group I such as VIP1 or PosF21 (also known as bZIP transcription factor 59) [, , , ].bZIP factors act in networks of homo and heterodimers in the regulation of a diverse set of cellular processes. The bZIP structural motif contains a basic region and a leucine zipper, composed of alpha helices with leucine residues 7 amino acids apart, which stabilize dimerization with a parallel leucine zipper domain. Dimerization of leucine zippers creates a pair of the adjacent basic regions that bind DNA and undergo conformational change. Dimerization occurs in a specific and predictable manner resulting in hundreds of dimers having unique effects on transcription [].
This entry represents the N-terminal domain found in a family of neurogenic mastermind-like proteins (MAMLs), which act as critical transcriptional co-activators for Notch signaling [, , ]. Notch receptors are cleaved upon ligand engagement and the intracellular domain of Notch shuttles to the nucleus. MAMLs form a functional DNA-binding complex with the cleaved Notch receptor and the transcription factor CSL, thereby regulating transcriptional events that are specific to the Notch pathway. MAML proteins may also play roles as key transcriptional co-activators in other signal transduction pathways as well, including: muscle differentiation and myopathies (MEF2C) [], tumour suppressor pathway (p53) []and colon carcinoma survival (beta-catenin) []. MAML proteins could mediate cross-talk among the various signaling pathways and the diverse activities of the MAML proteins converge to impact normal biological processes and human diseases, including cancers.The N-terminal domain of MAML proteins adopt an elongated kinked helix that wraps around ANK and CSL forming one of the complexes in the build-up of the Notch transcriptional complex for recruiting general transcription factors []. This N-terminal domain is responsible for its interaction with the ankyrin repeat region of the Notch proteins NOTCH1 [], NOTCH2 [], NOTCH3 []and NOTCH4. It forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1, and also binds CREBBP/CBP []and CDK8 []. The C-terminal region is required for transcriptional activation.
This family includes the neurogenic mastermind-like proteins 1-3 (MAML1-3) from chordates, which act as critical transcriptional co-activators for Notch signaling [, ]. Notch receptors are cleaved upon ligand engagement and the intracellular domain of Notch shuttles to the nucleus. MAMLs form a functional DNA-binding complex with the cleaved Notch receptor and the transcription factor CSL, thereby regulating transcriptional events that are specific to the Notch pathway. MAML proteins may also play roles as key transcriptional co-activators in other signal transduction pathways as well, including: muscle differentiation and myopathies (MEF2C) [], tumour suppressor pathway (p53) []and colon carcinoma survival (beta-catenin) []. MAML proteins could mediate cross-talk among the various signaling pathways and the diverse activities of the MAML proteins converge to impact normal biological processes and human diseases, including cancers.They consist of an N-terminal domain which adopt an elongated kinked helix that wraps around ANK and CSL forming one of the complexes in the build-up of the Notch transcriptional complex for recruiting general transcription factors [, ]]. This N-terminal domain is responsible for its interaction with the ankyrin repeat region of the Notch proteins NOTCH1 [], NOTCH2 [], NOTCH3 []and NOTCH4. It forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1, and also binds CREBBP/CBP []and CDK8 []. The C-terminal region is required for transcriptional activation.
Ribonuclease L (RNase L) is a highly regulated, latent endoribonuclease (thus the 'L' in RNase L) and is widely expressed in most mammalian tissues. It is involved in the mediation of the antiviral and pro-apoptotic activities of the interferon-inducible 2-5A system, which blocks infections by certain types of viruses through cleavage of viral and cellular single-stranded RNA [, ]. RNase L is unique in that it is composed of threemajor domains; N terminus regulatory ankyrin repeat domain (ARD), followed by a linker, a protein kinase (PK)-like domain and a C-terminal ribonuclease (RNase) domain. The RNase domain has homology with IRE1, also containing both a kinase and an endoribonuclease, that functions in the unfolded protein response (UPR) []. RNase L has been shown to have an impact on the pathogenesis of prostate cancer; the RNase L gene, RNASEL, has been identified as a strong candidate for the hereditary prostate cancer 1 (HPC1) allele [, , ]. The broad range of biological functions of RNase offers a possibility for RNase L as a therapeutic target.This entry represents the RNase domain of RNase L.
Positive-stranded RNA (RNA) viruses that belong to the order Nidovirales infect a wide range of vertebrates (families Arteriviridae and Coronaviridae) or invertebrates (Mesoniviridae and Roniviridae). Examples of nidoviruses with high economic and societal impact are the arterivirus porcine reproductive and respiratory syndrome virus (PRRSV) and the zoonotic coronaviruses (CoVs) causing severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and Covid-19 (SARS-CoV-2) in humans.The 3'-terminal region of the most conserved ORF1b in three of the four families of the order Nidovirales (except for the family Arteriviridae) encodes a 2'-O-methyltransferase (2'-O-MTase), known as non structural protein (NSP) 16 in CoV and implicated in methylation of the 5' cap structure of nidoviral mRNAs. Assembly of a cap1 structure at the 5' end of viral mRNA assists in translation and evading host defense. The cap structure consists of a 7-methylguanosine (m7G) linked to the first nucleotide of the RNA transcript through a 5'-5' triphosphate bridge. The CoV NSP16 methyltransferase forms an obligatory complex with NSP10 to efficiently convert client mRNA species from the cap-0 ((me7)G(0)pppA(1)) to the cap-1 form ((me7)G(0)pppA(1m)) by methylating the ribose 2'-O of the first nucleotide of the nascent mRNA using S-adenosyl methionine (SAM) as the methyl donor [, , , ].The nidovirus 2'-O-MTase domain exhibits the characteristic fold of the class I MTase family, comprising a β-sheet flanked by α-helices and loops. The nidovirus 2'-O-MTase domain harbors a catalytic K-D-K-E tetrad that is conserved among 2'-O-MTases [, , ].
This entry represents the N-terminal domain found in a family of neurogenic mastermind-like proteins (MAMLs), which act as critical transcriptional co-activators for Notch signaling [, , ]. Notch receptors are cleaved upon ligand engagement and the intracellular domain of Notch shuttles to the nucleus. MAMLs form a functional DNA-binding complex with the cleaved Notch receptor and the transcription factor CSL, thereby regulating transcriptional events that are specific to the Notch pathway. MAML proteins may also play roles as key transcriptional co-activators in other signal transduction pathways as well, including: muscle differentiation and myopathies (MEF2C) [], tumour suppressor pathway (p53) []and colon carcinoma survival (beta-catenin) []. MAML proteins could mediate cross-talk among the various signaling pathways and the diverse activities of the MAML proteins converge to impact normal biological processes and human diseases, including cancers.The N-terminal domain of MAML proteins adopt an elongated kinked helix that wraps around ANK and CSL forming one of the complexes in the build-up of the Notch transcriptional complex for recruiting general transcription factors []. This N-terminal domain is responsible for its interaction with the ankyrin repeat region of the Notch proteins NOTCH1 [], NOTCH2 [], NOTCH3 []and NOTCH4. It forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1, and also binds CREBBP/CBP []and CDK8 []. The C-terminal region is required for transcriptional activation.
The beta4 subunit of voltage-dependent calcium channels (Ca(V)s) is one of four beta subunits present in vertebrates. It is highly expressed in the brain, predominantly in the cerebellum []. Ca(V)s are multi-protein complexes that regulate the entry of calcium into cells. They impact muscle contraction, neuronal migration, hormone and neurotransmitter release, and the activation of calcium-dependent signaling pathways. They are composed of four subunits: alpha1, alpha2delta, beta, and gamma. The beta subunit is a soluble and intracellular protein that interacts with the transmembrane alpha1 subunit. It facilitates the trafficking and proper localization of the alpha1 subunit to the cellular plasma membrane []. Vertebrates contain four different beta subunits from distinct genes (beta1-4); each exists as multiple splice variants []. All are expressed in the brain while other tissues show more specific expression patterns. The beta subunits show similarity to MAGUK (membrane-associated guanylate kinase) proteins in that they contain SH3 and inactive guanylate kinase (GuK) domains; however, they do not appear to contain a PDZ domain [].This entry represents the SH3 domain of the subunit beta-3.
Polycystic kidney diseases (PKD) are disorders characterised by large numbers of cysts distributed throughout grossly-enlarged kidneys. Cystdevelopment is associated with impairment of kidney function, and ultimately kidney failure and death [, ]. Most cases of autosomal dominant PKD result from mutations in the PKD1 gene that cause premature protein termination. A second gene for autosomal dominant polycystic kidney disease has been identified by positional cloning []. The predicted 968-amino acid sequence of the PKD2 gene product (polycystin-2) contains 6 transmembrane domains, with intracellular N- and C-termini. Polycystin-2 shares some similarity with the family of voltage-activated calcium (and sodium) channels, and contains a potential calcium-binding domain [].Polycystin-2 is strongly expressed in ovary, foetal and adult kidney, testis, and small intestine. Polycystin-1 requires the presence of this protein for stable expression and is believed to interact with it via its C terminus. All mutations between exons 1 and 11 result in a truncated polycystin-2 that lacks a calcium-binding EF-hand domain and the cytoplasmic domains required for the interaction of polycystin-2 with polycystin-1 []. PKD2, although clinically milder than PKD1, has a deleterious impact on life expectancy.
Positive-stranded RNA (+RNA) viruses that belong to the order Nidovirales infect a wide range of vertebrates (families Arteriviridae and Coronaviridae) or invertebrates (Mesoniviridae and Roniviridae). Examples of nidoviruses with high economic and societal impact are the arterivirus porcine reproductive and respiratory syndrome virus (PRRSV) and the zoonotic coronaviruses (CoVs) causing severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and Covid-19 (SARS-CoV-2) in humans. In all nidoviruses, at least two-thirds of the capacity of the polycistronic genome is occupied by the two large open reading frames (ORFs; 1a and 1b) that together constitute the replicase gene. The two polyproteins produced, pp1a (ORF1a-encoded) and pp1ab (ORF1a/ORF1b-encoded), are processed to a dozen or more proteins by the virus main protease (3CLpro, encoded in ORF1a) with possible involvement of other protease(s). These and other proteins form a membrane-bound replication-transcription complex (RTC) that invariably includes two key ORF1b-encoded subunits: the RNA-dependent RNA polymerase (RdRp) and a superfamily 1 helicase domain (HEL1), which is fused with a multinuclear Zn-binding domain (ZBD). The RNA-dependent RNA polymerase (RdRp) domain of nidoviruses resides in a cleavage product of the replicase polyprotein named non- structural protein (nsp) 12 in coronaviruses and nsp9 in arteriviruses. In all nidoviruses, the C-terminal RdRp domain is linked to a conserved N-terminal domain, which has been coined NiRAN (nidovirus RdRp-associated nucleotidyl transferase). The NiRAN domain has an essential nucleotidylation activity and its potential functions in nidovirus replication may include RNA ligation, protein-primed RNA synthesis, and the guanylyl-transferase function that is necessary for mRNA capping [, , , , ].The NiRAN domain is characterised by an α+β fold composed of eight α-helices and a five stranded β-sheet. In addition, an N-terminal β-hairpin interacts with the palm subdomain of the RdRp domain [, ].
Polycystic kidney diseases (PKD) are disorders characterised by large numbers of cysts distributed throughout grossly-enlarged kidneys. Cystdevelopment is associated with impairment of kidney function, and ultimately kidney failure and death [, ]. Most cases of autosomal dominant PKD result from mutations in the PKD1 gene that cause premature protein termination. A second gene for autosomal dominant polycystic kidney disease has been identified by positional cloning []. The predicted 968-amino acid sequence of the PKD2 gene product (polycystin-2) contains 6 transmembrane domains, with intracellular N- and C-termini. Polycystin-2 shares some similarity with the family of voltage-activated calcium (and sodium) channels, and contains a potential calcium-binding domain [].Polycystin-2 is strongly expressed in ovary, foetal and adult kidney, testis, and small intestine. Polycystin-1 requires the presence of this protein for stable expression and is believed to interact with it via its C terminus. All mutations between exons 1 and 11 result in a truncated polycystin-2 that lacks a calcium-binding EF-hand domain and the cytoplasmic domains required for the interaction of polycystin-2 with polycystin-1 []. PKD2, although clinically milder than PKD1, has a deleterious impact on life expectancy.This entry contains proteins belonging to the polycystin family including Mucolipin and Polycystin-1 and -2 (PKD1 and PKD2). The domain contains the cation channel region of PKD1 and PKD2 proteins. PKD1 and PKD2 may function through a common signalling pathway that is necessary for normal tubulogenesis. The PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini [].Mucolipin is a cationic channel which probably plays a role in the endocytic pathway and in the control of membrane trafficking of proteins and lipids. It could play a major role in the calcium ion transport regulating lysosomal exocytosis [, , ].
The type I glycoprotein S of Coronavirus, trimers of which constitute the typical viral spikes, is assembled into virions through noncovalent interactions with the M protein. The spike glycoprotein is translated as a large polypeptide that is subsequently cleaved to S1 and S2 []. The cleavage of S can occur at two distinct sites: S2 or S2' []. The S1 subunit is responsible for host-receptor binding while the S2 subunit contains the membrane-fusion machinery [].Both chimeric S proteins appeared to cause cell fusion when expressed individually, suggesting that they were biologically fully active []. The spike is a type I membrane glycoprotein that possesses a conserved transmembrane anchor and an unusual cysteine-rich (cys) domain that bridges the putative junction of the anchor and the cytoplasmic tail [].The S2 subunit normally contains multiple key components, including one or more fusion peptides (FP), a second proteolytic site (S2') and two conserved heptad repeats (HRs), driving membrane penetration and virus-cell fusion. The HRs can trimerize into a coiled-coil structure built of three HR1-HR2 helical hairpins presenting as a canonical six-helix bundle and drag the virus envelope and the host cell bilayer into close proximity, preparing for fusion to occur []. The fusion core is composed of HR1 and HR2 and at least three membranotropic regions that are denoted as the fusion peptide (FP), internal fusion peptide (IFP), and pretransmembrane domain (PTM). The HR regions are further flanked by the three membranotropic components. Both FP and IFP are located upstream of HR1, while PTM is distally downstream of HR2 and directly precedes the transmembrane domain of SARS-CoV S. All of these three components are able to partition into the phospholipid bilayer to disturb membrane integrity. []. During the pandemic, many conservative amino acid changes in FP segment of SARS-CoV-2 have been reported (i.e., L821I, L822F, K825R, V826L, T827I, L828P, A829T, D830G/A, A831V/S/T, G832C/S, F833S, I834T), although their impact is not known as the active conformation and mode of insertion of SARS-CoV-2 fusion peptide have not been experimentally characterised. Differences in HR1 sequences between SARS-CoV and SARS-CoV-2 suggest that SARS-CoV-2 HR2 makes stronger interactions with HR1. However, the substitutions observed in the solvent accessible surface of the HR1 domain (e.g., D936Y, S943P, S939F) of SARS-CoV-2 do not seem to be involved in stabilizing interactions with HR2. Substitutions in HR2 (e.g., K1073N, V1176F) or the TM or cytoplasmic tail domains have also been observed, but further experimental work is required to determine the effects of these changes [].
Aquaporins are water channels, present in both higher and lower organisms, that belong to the major intrinsic protein family. Most aquaporins are highly selective for water, though some also facilitate the movement of small uncharged molecules such as glycerol []. In higher eukaryotes these proteins play diverse roles in the maintenance of water homeostasis, indicating that membrane water permeability can be regulated independently of solute permeability. In microorganisms however, many of which do not contain aquaporins, they do not appear to play such a broad role. Instead, they assist specific microbial lifestyles within the environment, e.g. they confer protection against freeze-thaw stress and may help maintain water permeability at low temperatures []. The regulation of aquaporins is complex, including transcriptional, post-translational, protein-trafficking and channel-gating mechanisms that are frequently distinct for each family member.Structural studies show that aquaporins are present in the membrane as tetramers, though each monomer contains its own channel [, , ]. The monomer has an overall "hourglass"structure made up of three structural elements: an external vestibule, an internal vestibule, and an extended pore which connects the two vestibules. Substrate selectivity is conferred by two mechanisms. Firstly, the diameter of the pore physically limits the size of molecules that can pass through the channel. Secondly, specific amino acids within the molecule regulate the preference for hydrophobic or hydrophilic substrates.Aquaporins are classified into two subgroups: the aquaporins (also known as orthodox aquaporins), which transport only water, and the aquaglyceroporins, which transport glycerol, urea, and other small solutes in addition to water [, ].Aquaporin-1 is the major water channel present in the kidney proximal renal tubule. Members of the family contain approximately 275 amino acids. Aquaporin-1 is under complex regulation, including hormones and homeostatic factors like hypertonicity []. It is also expressed in red blood cells, the gastrointestinal tract, lungs and in the brain, where it may have a role in cerebral oedema after surgery or trauma []. Apart from controlling the water balance of the organism [, ], aquaporin-1 is thought to have an impact onvarious cellular processes, such as angiogenesis, and cell migration and metastasis observed in some human malignancies. Its expression has also been proposed as a characteristic feature of an aggressive sub-group of breast carcinomas.
Histone proteins have central roles in both chromatin organisation (asstructural units of the nucleosome) and gene regulation (as dynamic componentsthat have a direct impact on DNA transcription and replication). EukaryoticDNA wraps around a histone octamer to form a nucleosome, the first order ofcompaction of eukaryotic chromatin. The core histone octamer is composed of acentral H3-H4 tetramer and two flanking H2A-H2B dimers. Each of the corehistone contains a common structural motif, called the histone fold, whichfacilitates the interactions between the individual core histones.In addition to the core histones, there is a "linker histone"called H1 (or H5 in avian species). The linker histones present in all multicellular eukaryotes are the most divergent group of histones, with numerous cell type- and stage-specific variant. Linker histone H1 is an essential component of chromatin structure. H1 links nucleosomes into higher order structures.Histone H5 performs the same function as histone H1, and replaces H1 in certain cells. The structure of GH5, the globular domain of the linker histone H5 is known [, ]. The fold is similar to the DNA-binding domain of the catabolite gene activator protein, CAP, thus providing a possible model for the binding of GH5 to DNA.The linker histones, which do not contain the histone fold motif, are critical to the higher-order compaction of chromatin, because they bind to internucleosomal DNA and facilitate interactions between individual nucleosomes. In addition, H1 variants have been shown to be involved in the regulation of developmental genes. A common feature of this protein family is a tripartite structure in which a globular (H15) domain of about 80 amino acids is flanked by two less structured N- and C-terminal tails. The H15domain is also characterised by high sequence homology among the family oflinker histones. The highly conserved H15 domain is essential for the bindingof H1 or H5 to the nucleosome. It consists of a three helix bundle (I-III),with a β-hairpin at the C terminus. There is also a short three-residuestretch between helices I and II that is in the β-strand conformation.Together with the C-terminal β-hairpin, this strand forms the third strandof an antiparallel β-sheet [, , , ].Histone H5 is a nuclear protein involved in the condensation of nucleosome chains into higher order structures. In this respect, it performs the same function as histone H1, and replaces H1 in certain cells. The structure of GH5, the globular domain (residues 22-100) of the linker histone H5, has been solved. The fold is similar to the DNA-binding domain of the catabolite gene activator protein, CAP, thus providing a possible model for the binding of GH5 to DNA. The structure comprises 3 α-helices and 2 short β-strands [, ].
Histone proteins have central roles in both chromatin organisation (asstructural units of the nucleosome) and gene regulation (as dynamic componentsthat have a direct impact on DNA transcription and replication). EukaryoticDNA wraps around a histone octamer to form a nucleosome, the first order ofcompaction of eukaryotic chromatin. The core histone octamer is composed of acentral H3-H4 tetramer and two flanking H2A-H2B dimers. Each of the corehistone contains a common structural motif, called the histone fold, whichfacilitates the interactions between the individual core histones.In addition to the core histones, there is a "linker histone"called H1 (or H5 in avian species). The linker histones present in all multicellular eukaryotes are the most divergent group of histones, with numerous cell type- and stage-specific variant. Linker histone H1 is an essential component of chromatin structure. H1 links nucleosomes into higher order structures.Histone H5 performs the same function as histone H1, and replaces H1 in certain cells. The structure of GH5, the globular domain of the linker histone H5 is known [, ]. The fold is similar to the DNA-binding domain of the catabolite gene activator protein, CAP, thus providing a possible model for the binding of GH5 to DNA.The linker histones, which do not contain the histone fold motif, are critical to the higher-order compaction of chromatin, because they bind to internucleosomal DNA and facilitate interactions between individual nucleosomes. In addition, H1 variants have been shown to be involved in the regulation of developmental genes. A common feature of this protein family is a tripartite structure in which a globular (H15) domain of about 80 amino acids is flanked by two less structured N- and C-terminal tails. The H15domain is also characterised by high sequence homology among the family oflinker histones. The highly conserved H15 domain is essential for the bindingof H1 or H5 to the nucleosome. It consists of a three helix bundle (I-III),with a β-hairpin at the C terminus. There is also a short three-residuestretch between helices I and II that is in the β-strand conformation.Together with the C-terminal β-hairpin, this strand forms the third strandof an antiparallel β-sheet [, , , ].Proteins known to contain a H15 domain are:- Eukaryotic histone H1. The histones H1 constitute a family with many variants, differing in their affinity for chromatin. Several variants aresimultaneously present in a single cell. For example, the nucleatederythrocytes of birds contain both H1 and H5, the latter being an extremevariant of H1.- Eukaryotic MHYST family of histone acetyltransferase. Histoneacetyltransferases transfer an acetyl group from acetyl-CoA to the epsylon-amino group of lysine within the basic NH2-termini of histones, which bindthe acidic phosphates of DNA [].This entry represents the H15 domain.
Fish allergies are common in Europe, particularly among male children and young adults. Children allergic to fish react variably todifferent species.Cod is among the most common offenders, while salmon is the one besttolerated. The allergy-eliciting protein has been isolated from the whitemuscle albumin. It is a parvalbumin, designated Allergen M. Parvalbumins arecalcium (Ca)-binding proteins of low molecular weight. Like many other Ca-binding proteins, they belong to the EF-hand family characterised byhelix-loop-helix (HLH) binding motifs (two helices pack together at an angleof ~90 degrees, separated by a loop region where calcium binds). In the parvalbumin HLH structural motif, calcium is coordinated through one carbonyl oxygen atom and the oxygen-containing side-chains of 5 amino acidresidues, or 4 residues and a water molecule[, , ].Initially, parvalbumins were detected in relatively high amounts in lowervertebrate white muscle, where they were thought to be important for fibrerelaxation. They were subsequently found, although in lesser amounts, in thefast twitch skeletal muscles of higher vertebrates, as well as in a varietyof non-muscle tissues, including testis, endocrine glands, skin and specificneurons. There are two distinct phylogenetic lineages: alpha and beta. Mostmuscles contain parvalbumin of only alpha or beta origin. Cod parvalbumin belongs to the beta-lineage and shares significant similarity with parvalbumin of other fish species [, ].Allergen M contains 113 residues, is a homogenous acidic protein and belongsto a group of muscle sarcoplasmic proteins. It carries the major allergenicdeterminants associated with cod sensitivity, which is dependent directly onthe linear structure rather than on the molecular conformation. The allergenic activity of allergen M resides in particular epitopes found inthree loops: AB (~13-33), CD (~48-64) and EF (~80-103). It has an N-acetylterminal amino acid residue and includes 1 residue of glucose attached to the conserved N-terminal cysteine, and 1 residue each of tyrosine, tryptophan and arginine - the arginine is believed to play a key role in maintaining the tertiary structure. Mutation of the last conservedcoordinating residue of the Ca-binding loop (E101D-motif 4) has also beenshown to have a significant impact on the ability of the mutant to obtainthe sevenfold coordination preferred by Ca2+.
The type I glycoprotein S of Coronavirus, trimers of which constitute the typical viral spikes, is assembled into virions through noncovalent interactions with the M protein. The spike glycoprotein is translated as a large polypeptide that is subsequently cleaved to S1 () and S2 []. The cleavage of S can occur at two distinct sites: S2 or S2' []. The spike is present in two very different forms: pre-fusion (the form on mature virions) and post-fusion (the form after membrane fusion has been completed). The spike is cleaved sequentially by host proteases at two sites: first at the S1/S2 boundary (i.e. S1/S2 site) and second within S2 (i.e. S2' site). After the cleavages, S1 dissociates from S2, allowing S2 to transition to the post-fusion structure []. Both chimeric S proteins appeared to cause cell fusion when expressed individually, suggesting that they were biologically fully active []. The spike is a type I membrane glycoprotein that possesses a conserved transmembrane anchor and an unusual cysteine-rich (cys) domain that bridges the putative junction of the anchor and the cytoplasmic tail [].SARS-CoV S is largely uncleaved after biosynthesis. It can be later processed by endosomal cathepsin L, trypsin, thermolysin, and elastase, which are shown to induce syncytia formation and virus entry. Other proteases that are of potential biological relevance in potentiating SARS-CoV S include TMPRSS2, TMPRSS11a, and HAT which are localized on the cell surface and are highly expressed in the human airway []. The furin-like S2' cleavage site at KR/SF with P1 and P2 basic residues and a P2' hydrophobic Phe downstream of the IFP is identical between the SARS-CoV-2 and SARS-CoV. One or more furin-like enzymes would cleave the S2' site at KR/SF [, ]. Deletion of SARS-CoV-2 furin cleavage site suggests that it may not be required for viral entry but may affect replication kinetics and altered sites have been still seen proteolytically cleaved. Several substitutions within the S2' cleavage domain of SARS-COV-2 have been reported, including P812L/S/T, S813I/G, F817L, I818S/V, but further experimental study of their consequences and the replication properties of the altered viruses are required to understand the role of furin cleavage in SARS-CoV-2 infection and virulence []. The S2 subunit normally contains multiple key components, including one or more fusion peptides (FP), a second proteolytic site (S2') and two conserved heptad repeats (HRs), driving membrane penetration and virus-cell fusion. The HRs can trimerize into a coiled-coil structure built of three HR1-HR2 helical hairpins presenting as a canonical six-helix bundle and drag the virus envelope and the host cell bilayer into close proximity, preparing for fusion to occur []. The fusion core is composed of HR1 and HR2 and at least three membranotropic regions that are denoted as the fusion peptide (FP), internal fusion peptide (IFP), and pretransmembrane domain (PTM). The HR regions are further flanked by the three membranotropic components. Both FP and IFP are located upstream of HR1, while PTM is distally downstream of HR2 and directly precedes the transmembrane domain of SARS-CoV S. All of these three components are able to partition into the phospholipid bilayer to disturb membrane integrity. []. During the pandemic, many conservative amino acid changes in FP segment of SARS-CoV-2 have been reported (i.e., L821I, L822F, K825R, V826L, T827I, L828P, A829T, D830G/A, A831V/S/T, G832C/S, F833S, I834T), although their impact is not known as the active conformation and mode of insertion of SARS-CoV-2 fusion peptide have not been experimentally characterised. Differences in HR1 sequences between SARS-CoV and SARS-CoV-2 suggest that SARS-CoV-2 HR2 makes stronger interactions with HR1. However, the substitutions observed in the solvent accessible surface of the HR1 domain (e.g., D936Y, S943P, S939F) of SARS-CoV-2 do not seem to be involved in stabilizing interactions with HR2. Substitutions in HR2 (e.g., K1073N, V1176F) or the TM or cytoplasmic tail domains have also been observed, but further experimental work is required to determine the effects of these changes [].
The type I glycoprotein S of Coronavirus, trimers of which constitute the typical viral spikes, is assembled into virions through noncovalent interactions with the M protein. The spike glycoprotein is translated as a large polypeptide that is subsequently cleaved to S1 () and S2 []. The cleavage of S can occur at two distinct sites: S2 or S2' []. The spike is present in two very different forms: pre-fusion (the form on mature virions) and post-fusion (the form after membrane fusion has been completed). The spike is cleaved sequentially by host proteases at two sites: first at the S1/S2 boundary (i.e. S1/S2 site) and second within S2 (i.e. S2' site). After the cleavages, S1 dissociates from S2, allowing S2 to transition to the post-fusion structure []. Both chimeric S proteins appeared to cause cell fusion when expressed individually, suggesting that they were biologically fully active []. The spike is a type I membrane glycoprotein that possesses a conserved transmembrane anchor and an unusual cysteine-rich (cys) domain that bridges the putative junction of the anchor and the cytoplasmic tail [].SARS-CoV S is largely uncleaved after biosynthesis. It can be later processed by endosomal cathepsin L, trypsin, thermolysin, and elastase, which are shown to induce syncytia formation and virus entry. Other proteases that are of potential biological relevance in potentiating SARS-CoV S include TMPRSS2, TMPRSS11a, and HAT which are localized on the cell surface and are highly expressed in the human airway []. The furin-like S2' cleavage site at KR/SF with P1 and P2 basic residues and a P2' hydrophobic Phe downstream of the IFP is identical between the SARS-CoV-2 and SARS-CoV. One or more furin-like enzymes would cleave the S2' site at KR/SF [, ]. Deletion of SARS-CoV-2 furin cleavage site suggests that it may not be required for viral entry but may affect replication kinetics and altered sites have been still seen proteolytically cleaved. Several substitutions within the S2' cleavage domain of SARS-COV-2 have been reported, including P812L/S/T, S813I/G, F817L, I818S/V, but further experimental study of their consequences and the replication properties of the altered viruses are required to understand the role of furin cleavage in SARS-CoV-2 infection and virulence []. The S2 subunit normally contains multiple key components, including one or more fusion peptides (FP), a second proteolytic site (S2') and two conserved heptad repeats (HRs), driving membrane penetration and virus-cell fusion. The HRs can trimerize into a coiled-coil structure built of three HR1-HR2 helical hairpins presenting as a canonical six-helix bundle and drag the virus envelope and the host cell bilayer into close proximity, preparing for fusion to occur []. The fusion core is composed of HR1 and HR2 and at least three membranotropic regions that are denoted as the fusion peptide (FP), internal fusion peptide (IFP), and pretransmembrane domain (PTM). The HR regions are further flanked by the three membranotropic components. Both FP and IFP are located upstream of HR1, while PTM is distally downstream of HR2 and directly precedes the transmembrane domain of SARS-CoV S. All of these three components are able to partition into the phospholipid bilayer to disturb membrane integrity. []. During the pandemic, many conservative amino acid changes in FP segment of SARS-CoV-2 have been reported (i.e., L821I, L822F, K825R, V826L, T827I, L828P, A829T, D830G/A, A831V/S/T, G832C/S, F833S, I834T), although their impact is not known as the active conformation and mode of insertion of SARS-CoV-2 fusion peptide have not been experimentally characterised. Differences in HR1 sequences between SARS-CoV and SARS-CoV-2 suggest that SARS-CoV-2 HR2 makes stronger interactions with HR1. However, the substitutions observed in the solvent accessible surface of the HR1 domain (e.g., D936Y, S943P, S939F) of SARS-CoV-2 do not seem to be involved in stabilizing interactions with HR2. Substitutions in HR2 (e.g., K1073N, V1176F) or the TM or cytoplasmic tail domains have also been observed, but further experimental work is required to determine the effects of these changes [].This entry represents the cysteine rich intravirion region found at the C-terminal of coronavirus spike proteins (S) []. These cysteine residues are targets for palmitoylation, necessary for efficiently S incorporation into virions and S-mediated membrane fusions.
The type I glycoprotein S of Coronavirus, trimers of which constitute the typical viral spikes, is assembled into virions through noncovalent interactions with the M protein. The spike glycoprotein is translated as a large polypeptide that is subsequently cleaved to S1 () and S2 []. The cleavage of S can occur at two distinct sites: S2 or S2' []. The spike is present in two very different forms: pre-fusion (the form on mature virions) and post-fusion (the form after membrane fusion has been completed). The spike is cleaved sequentially by host proteases at two sites: first at the S1/S2 boundary (i.e. S1/S2 site) and second within S2 (i.e. S2' site). After the cleavages, S1 dissociates from S2, allowing S2 to transition to the post-fusion structure []. Both chimeric S proteins appeared to cause cell fusion when expressed individually, suggesting that they were biologically fully active []. The spike is a type I membrane glycoprotein that possesses a conserved transmembrane anchor and an unusual cysteine-rich (cys) domain that bridges the putative junction of the anchor and the cytoplasmic tail [].SARS-CoV S is largely uncleaved after biosynthesis. It can be later processed by endosomal cathepsin L, trypsin, thermolysin, and elastase, which are shown to induce syncytia formation and virus entry. Other proteases that are of potential biological relevance in potentiating SARS-CoV S include TMPRSS2, TMPRSS11a, and HAT which are localized on the cell surface and are highly expressed in the human airway []. The furin-like S2' cleavage site at KR/SF with P1 and P2 basic residues and a P2' hydrophobic Phe downstream of the IFP is identical between the SARS-CoV-2 and SARS-CoV. One or more furin-like enzymes would cleave the S2' site at KR/SF [, ]. Deletion of SARS-CoV-2 furin cleavage site suggests that it may not be required for viral entry but may affect replication kinetics and altered sites have been still seen proteolytically cleaved. Several substitutions within the S2' cleavage domain of SARS-COV-2 have been reported, including P812L/S/T, S813I/G, F817L, I818S/V, but further experimental study of their consequences and the replication properties of the altered viruses are required to understand the role of furin cleavage in SARS-CoV-2 infection and virulence []. The S2 subunit normally contains multiple key components, including one or more fusion peptides (FP), a second proteolytic site (S2') and two conserved heptad repeats (HRs), driving membrane penetration and virus-cell fusion. The HRs can trimerize into a coiled-coil structure built of three HR1-HR2 helical hairpins presenting as a canonical six-helix bundle and drag the virus envelope and the host cell bilayer into close proximity, preparing for fusion to occur []. The fusion core is composed of HR1 and HR2 and at least three membranotropic regions that are denoted as the fusion peptide (FP), internal fusion peptide (IFP), and pretransmembrane domain (PTM). The HR regions are further flanked by the three membranotropic components. Both FP and IFP are located upstream of HR1, while PTM is distally downstream of HR2 and directly precedes the transmembrane domain of SARS-CoV S. All of these three components are able to partition into the phospholipid bilayer to disturb membrane integrity. []. During the pandemic, many conservative amino acid changes in FP segment of SARS-CoV-2 have been reported (i.e., L821I, L822F, K825R, V826L, T827I, L828P, A829T, D830G/A, A831V/S/T, G832C/S, F833S, I834T), although their impact is not known as the active conformation and mode of insertion of SARS-CoV-2 fusion peptide have not been experimentally characterised. Differences in HR1 sequences between SARS-CoV and SARS-CoV-2 suggest that SARS-CoV-2 HR2 makes stronger interactions with HR1. However, the substitutions observed in the solvent accessible surface of the HR1 domain (e.g., D936Y, S943P, S939F) of SARS-CoV-2 do not seem to be involved in stabilizing interactions with HR2. Substitutions in HR2 (e.g., K1073N, V1176F) or the TM or cytoplasmic tail domains have also been observed, but further experimental work is required to determine the effects of these changes [].This entry represents the heptad repeat 1 (HR1) from coronavirus Spike glycoprotein, S2 subunit. This region forms a long trimeric helical coiled-coil structure with peptides from the HR2 region packing in an oblique antiparallel manner on the grooves of the HR1 trimer in a mixed extended and helical conformation. Packing of the helical parts of HR2 on the HR1 trimer grooves and formation of a six-helical bundle plays an important role in the formation of a stable post-fusion structure. In contrast to their extended helical conformations in the post-fusion state, the HR1 motifs within S2 form several shorter helices in their pre-fusion state [, ].
The type I glycoprotein S of Coronavirus, trimers of which constitute the typical viral spikes, is assembled into virions through noncovalent interactions with the M protein. The spike glycoprotein is translated as a large polypeptide that is subsequently cleaved to S1 () and S2 []. The cleavage of S can occur at two distinct sites: S2 or S2' []. The spike is present in two very different forms: pre-fusion (the form on mature virions) and post-fusion (the form after membrane fusion has been completed). The spike is cleaved sequentially by host proteases at two sites: first at the S1/S2 boundary (i.e. S1/S2 site) and second within S2 (i.e. S2' site). After the cleavages, S1 dissociates from S2, allowing S2 to transition to the post-fusion structure []. Both chimeric S proteins appeared to cause cell fusion when expressed individually, suggesting that they were biologically fully active []. The spike is a type I membrane glycoprotein that possesses a conserved transmembrane anchor and an unusual cysteine-rich (cys) domain that bridges the putative junction of the anchor and the cytoplasmic tail [].SARS-CoV S is largely uncleaved after biosynthesis. It can be later processed by endosomal cathepsin L, trypsin, thermolysin, and elastase, which are shown to induce syncytia formation and virus entry. Other proteases that are of potential biological relevance in potentiating SARS-CoV S include TMPRSS2, TMPRSS11a, and HAT which are localized on the cell surface and are highly expressed in the human airway []. The furin-like S2' cleavage site at KR/SF with P1 and P2 basic residues and a P2' hydrophobic Phe downstream of the IFP is identical between the SARS-CoV-2 and SARS-CoV. One or more furin-like enzymes would cleave the S2' site at KR/SF [, ]. Deletion of SARS-CoV-2 furin cleavage site suggests that it may not be required for viral entry but may affect replication kinetics and altered sites have been still seen proteolytically cleaved. Several substitutions within the S2' cleavage domain of SARS-COV-2 have been reported, including P812L/S/T, S813I/G, F817L, I818S/V, but further experimental study of their consequences and the replication properties of the altered viruses are required to understand the role of furin cleavage in SARS-CoV-2 infection and virulence []. The S2 subunit normally contains multiple key components, including one or more fusion peptides (FP), a second proteolytic site (S2') and two conserved heptad repeats (HRs), driving membrane penetration and virus-cell fusion. The HRs can trimerize into a coiled-coil structure built of three HR1-HR2 helical hairpins presenting as a canonical six-helix bundle and drag the virus envelope and the host cell bilayer into close proximity, preparing for fusion to occur []. The fusion core is composed of HR1 and HR2 and at least three membranotropic regions that are denoted as the fusion peptide (FP), internal fusion peptide (IFP), and pretransmembrane domain (PTM). The HR regions are further flanked by the three membranotropic components. Both FP and IFP are located upstream of HR1, while PTM is distally downstream of HR2 and directly precedes the transmembrane domain of SARS-CoV S. All of these three components are able to partition into the phospholipid bilayer to disturb membrane integrity. []. During the pandemic, many conservative amino acid changes in FP segment of SARS-CoV-2 have been reported (i.e., L821I, L822F, K825R, V826L, T827I, L828P, A829T, D830G/A, A831V/S/T, G832C/S, F833S, I834T), although their impact is not known as the active conformation and mode of insertion of SARS-CoV-2 fusion peptide have not been experimentally characterised. Differences in HR1 sequences between SARS-CoV and SARS-CoV-2 suggest that SARS-CoV-2 HR2 makes stronger interactions with HR1. However, the substitutions observed in the solvent accessible surface of the HR1 domain (e.g., D936Y, S943P, S939F) of SARS-CoV-2 do not seem to be involved in stabilizing interactions with HR2. Substitutions in HR2 (e.g., K1073N, V1176F) or the TM orcytoplasmic tail domains have also been observed, but further experimental work is required to determine the effects of these changes [].This entry represents the heptad repeat 2 (HR2) from coronavirus Spike glycoprotein, S2 subunit. It adopts a mixed conformation: the central part fold into a nine-turn α-helix, while the residues on either side of the helix adopt an extended conformation. Packing of the helical parts of HR2 on the HR1 trimer grooves and formation of a six-helical bundle plays an important role in the formation of a stable post-fusion structure [, ].
