Adrenocortical dysplasia protein (acd, also known as TPP1) is a component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways []. It also forms a heterodimer with POT1 that increases the activity and processivity of the telomerase core enzyme [].This entry also includes fission yeast TPP1 homologue, Tpz1. Together with Pot1 it forms a complex that protects telomeres and regulates telomere length [].
This entry represents the alpha-crystallin domain (ACD) found in the small heat shock protein (sHsp) alphaB-crystallin (HspB5, 20kDa).sHsps are molecular chaperones that suppress protein aggregation and protect against cell stress, and are generally active as large oligomers consisting of multiple subunits [, ]. They are characterised by the presence of an alpha-crystallin domain [].Alpha crystallin, an abundant protein in the mammalian lens, is a large (700kDa) heteropolymer composed of HspB4 and HspB5, generally in a molar ratio of HspB4:HspB5 of 3:1. HspB5 shows increased synthesis in response to stress. HspB5 is also expressed constitutively in other tissues including brain, heart, and type I and type IIa skeletal muscle fibres, and in several cancers including gliomas, renal cell carcinomas, basal-like and metaplastic breast carcinomas, and head and neck cancer. Its functions include effects on the apoptotic pathway and on metastasis. Phosphorylation of HspB5 reduces its oligomerization and anti-apoptotic activities. HspB5 is protective in demyelinating disease such as multiple sclerosis (MS), being a negative regulator of inflammation []. In early active MS lesions it is the most abundant gene transcript and an autoantigen, the immune response against it would disrupt its function and worsen inflammation anddemyelination. Given as therapy for ongoing demyelinating disease it may counteract this effect []. It is an autoantigen in the pathogenesis of various other inflammatory disorders including Lens-associated uveitis (LAU), and Behcet's disease [, ]. Mutations in HspB5 have been associated with diseases including dominant cataract and desmin-related myopathy [].
This entry represents the alpha crystallin domain (ACD) found in mammalian Hsp27 (also denoted HspB1 in human).Small heat shock proteins (sHsps) are molecular chaperones that suppress protein aggregation and protect against cell stress, and are generally active as large oligomers consisting of multiple subunits [, ]. They are characterised by the presence of an alpha crystallin domain (ACD) [].Hsp27 shows enhanced synthesis in response to stress. It is a molecular chaperone which interacts with a large number of different proteins. It is found in many types of human cells including breast, uterus, cervix, platelets and cancer cells. Hsp27 has diverse cellular functions including chaperoning, regulation of actin polymerization, keratinocyte differentiation, regulation of inflammatory pathways in keratinocytes, and protection from oxidative stress through modulating glutathione levels [, , , ]. It is also a subunit of AUF1-containing protein complexes []. Hsp27 has been linked to several transduction pathways regulating cellular functions including differentiation, cell growth, development, and apoptosis []. Its activity can be regulated by phosphorylation. Its unphosphorylated state is a high molecular weight aggregated form (100-800kDa) composed of up to 24 subunits, which forms as a result of multiple interactions within the ACD, and is required for chaperone function and resistance to oxidative stress. Upon phosphorylation these large aggregates rapidly disassociate to smaller oligomers and chaperone activity is modified [].High constitutive levels of Hsp27 have been detected in various cancer cells, in particular those of carcinoma origin []. Over-expression of Hsp27 has a protective effect against various diseases-processes, including Huntington's disease []. Mutations in Hsp27 have been associated with a form of distal hereditary motor neuropathy type II and Charcot-Marie-Tooth disease type 2 [].
This entry represents the alpha crystallin domain (ACD) found in mammalian small heat shock protein (sHsp) HspB7, also known as cardiovascular small heat shock protein (cvHsp).Small Hsps are molecular chaperones that suppress protein aggregation and protect against cell stress, and are generally active as large oligomers consisting of multiple subunits []. HspB7 is a 25kDa protein, preferentially expressed in heart and skeletal muscle []. It is essential for fetal heart development by modulating actin filament assembly []. It binds the cytoskeleton protein alpha-filamin (also known as actin-binding protein 280) []. The expression of HspB7 is increased during rat muscle aging []. As the human gene encoding HspB7 is mapped to chromosome 1p36.23-p34.3 it is a positional candidate for several dystrophies and myopathies [].
This is the alpha-crystallin domain (ACD) found in Escherichia coli inclusion body-associated proteins IbpA and IbpB, and similar proteins. This domain is also found in class A small heat shock proteins from Bradyrhizobium, which consists of proteins that show similarity to E. coli IbpA and IbpB [].IbpA and IbpB are 16kDa small heat shock proteins (sHsps). sHsps are molecular chaperones that suppress protein aggregation and protect against cell stress, and are generally active as large oligomers consisting of multiple subunits. They all contain a conserved alpha-crystallin domain flanked by variable N- and C-terminal tails []. IbpA and IbpB are produced during high-level production of various heterologous proteins, specifically human prorenin, renin and bovine insulin-like growth factor 2 (bIGF-2), and are strongly associated with inclusion bodies containing these heterologous proteins []. IbpA and IbpB work as an integrated system to stabilize thermally aggregated proteins in a disaggregation competent state []. The chaperone activity of IbpB is also significantly elevated as the temperature increases from normal to heat shock. The high temperature results in the disassociation of 2-3-MDa IbpB oligomers into smaller approximately 600kDa structures. This elevated activity seen under heat shock conditions is retained for an extended period of time after the temperature is returned to normal []. IbpA also forms multimers [].
Acetyl coenzyme A (acetyl-CoA) synthetases (ACDs) were first described in Pyrococcus furiosus and then in other Archaea members as the major energy-conserving enzymes. They catalyse the reversible formation of acetate and ATP from acetyl-CoA by using ADP and phosphate and are able to use other substrates such as phenylacetyl-CoA, indoleacetyl-CoA and isobutyryl-CoA, but not succinyl-CoA. They are involved in the conversion of acetyl-CoA to acetate and in the degradation of branched-chain amino acids via branched-chain-acyl-CoA esters. There are two isoforms ACD I and II which are heterotetramers (alpha2beta2) consisting of two different subunits, alpha and beta [, , ]. Each ACD is composed of at least five subdomains with variable sequential arrangement, termed "domain shuffling", which confers a very diverse pattern of subdomain organisation within members of the ACD family.This entry represents the C-terminal domain of the Acetate--CoA ligase [ADP-forming]subunit alpha which corresponds to the ligase CoA domain and adopts a flavodoxin fold [].
Actin cross-linking domains (ACDs) are distinct domains found in several bacterial toxins, including the Vibrio cholerae MARTX toxin. ACDs are enzyme ligases that catalyse the formation of an irreversible iso-peptide bond on two actin molecules in an ATP- and Mg/Mn(2+)-dependent manner. Cross-linking depletes the cellular pool of G-actin leading to actin cytoskeleton depolymerisation [, ].The ACD has an overall V-shape. with the active site composed of five residues in a cleft located within the two arms of the V. The first subdomain, forming the left arm of the V, is mainly composed of β-strands, while the second subdomain, forming the right arm of the V, is helical. The first subdomain is composed of a central anti-parallel β-sheet of 8 β-strands, decorated by two adjacent small β-sheets, one above the centralβ-sheet and the second below. A long helix (α1) packs against strands β7-β4-βa5 from the central β-sheet, and strand β8 from the upper β-sheet. Finally, the terminal helix α9 packs against strands β2 and β9. The second subdomain is composed of 7 α-helices (α2-α8) and does not contain any β-strands [].
TPP1 (Est3 in yeast) is a component of the telomerase holoenzyme (shelterin complex), involved in telomere replication. It has been demonstrated that TPP1 dimerises and binds to DNA and RNA. Furthermore, TPP1 stimulates the dissociation of RNA/DNA hetero-duplexes [, ]. Yeast telomerase protein TPP1 (Est3) is a novel type of GTPase []. The key residues in Saccharomyces cerevisiae are an Asp at residue 86 and the Arg at residue 110. The Asp is totally conserved in the family, whereas the Arg is not so well conserved. The N-terminal of TPP1 is likely to be the binding surface for TIN2, whereas the C terminus probably binds to POT1, thereby tethering POT1 to the shelterin complex []. The complex bound to telomeric DNA increases the activity and processivity of the human telomerase core enzyme, thus helping to maintain the length of the telomeres [, , ].The human shelterin complex includes six proteins: telomere repeat binding factor 1 (TRF1); TRF2, repressor/activator protein 1 (RAP1); TRF1-interacting nuclear protein 2 (TIN2); TIN2-interacting protein 1 (TPP1), also known as ACD from adrenocortical dysplasia protein; and protection of telomeres 1 (POT1) [].
