RNF141, also known as zinc finger protein 230 (ZNF230), is a RING finger protein present primarily in the nuclei of spermatogonia, the acrosome, and the tail of spermatozoa []. It may have a broad function during early development of vertebrates. It plays an important role in spermatogenesis, including spermatogenic cell proliferation and sperm maturation, as well as motility and fertilization []. It also exhibits DNA binding activity [, ]. RNF141 corresponding ZNF230 gene mutation may be associated with azoospermia []. RNF141 contains a C3HC4-type RING finger domain that may function as an activator module in transcription [].
RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling []. It contains an N-terminal RING domain followed by a WWE domain that binds iso-ADPr. RNF146 is a RING E3 ligase whose activities are regulated by non-covalent ligand binding [].This entry represents the N-terminal C3HC4-type RING-HC finger found in RNF146 [].
TIF1-beta, also known as Kruppel-associated Box (KRAB)-associated protein 1 (KAP-1), belongs to the C-VI subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a plant homeodomain (PHD), and a bromodomain (Bromo) positioned C-terminal to the RBCC domain. It acts as a nuclear co-repressor that plays a role in transcription and in the DNA damage response [, , ]. Upon DNA damage, the phosphorylation of KAP-1 on serine 824 by the ataxia telangiectasia-mutated (ATM) kinase enhances cell survival and facilitates chromatin relaxation and heterochromatic DNA repair []. It also regulates CHD3 nucleosome remodelling during the DNA double-strand break (DSB) response []. Meanwhile, KAP-1 can be dephosphorylated by protein phosphatase PP4C in the DNA damage response []. Moreover, KAP-1 is a co-activator of the orphan nuclear receptor NGFI-B (or Nur77) and is involved in NGFI-B-dependent transcription []. It is also a coiled-coil binding partner, substrate and activator of the c-Fes protein tyrosine kinase []. The N-terminal RBCC domains of TIF1-beta are responsible for the interaction with KRAB zinc finger proteins (KRAB-ZFPs), MDM2, MM1, C/EBPbeta, and the regulation of homo- and heterodimerization []. The C-terminal PHD/Bromo domains are involved in interacting with SETDB1, Mi-2alpha and other proteins to form complexes with histone deacetylase or methyltransferase activity [, ].This entry represents the RING-HC finger found in TIF1-beta.
TRIM54, also known as MuRF-3, is an E3 ubiquitin-protein ligase involved in ubiquitin-mediated muscle protein turnover. It is ubiquitously detected in all fibre types, and is developmentally upregulated, associates with microtubules, the sarcomeric M-line (this report) and Z-line, and is required for microtubule stability and myogenesis. It associates with glutamylated microtubules during skeletal muscle development, and is required for skeletal myoblast differentiation and development of cellular microtubular networks. MuRF-3 controls the degradation of four-and-a-half LIM domain (FHL2) and gamma-filamin and is required for maintenance of ventricular integrity after myocardial infarction (MI) [, , ]. MuRF-3 belongs to the C-II subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox2, and a coiled coil region, as well as a COS (carboxyl-terminal subgroup one signature) box, and an acidic residue-rich (AR) domain. It also harbours a MURF family-specific conserved box (MFC) between its RING-HC finger and Bbox domains.This entry represents the C3HC4-type RING-HC finger found in MuRF-3 (TRIM54).
Hakai is an E3 ubiquitin ligase that disrupts cell-cell contacts in epithelial cells and is upregulated in human colon and gastric adenocarcinomas. It was identified to mediate the posttranslational downregulation of E-cadherin (CDH1), a major component of adherens junctions in epithelial cells and a potent tumour suppressor [, , ]. It also promotes ubiquitination of several other tyrosine-phosphorylated Src substrates, including cortactin (CTTN) and DOK1 []. Hakai acts as a homodimer with a novel HYB (Hakai pTyr-binding) domain that forms a phosphotyrosine-binding pocket upon, and consists of a pair of monomers arranged in an anti-parallel configuration. Each monomer contains a C3HC4-type RING-HC finger and a short pTyr-B domain that incorporates a novel, atypical C2H2-type Zn-finger coordination motif. Both domains are important for dimerization [, ]. ZNF645, also known as CBLL2, is a novel testis-specific E3 ubiquitin-protein ligase that plays a role in sperm production and quality control []. It has a structure similar to that of the c-Cbl-like protein Hakai. In contrast to Hakai, its HYB domain demonstrates different target specificities. It interacts with v-Src-phosphorylated E-cadherin, but not to cortactin [].
RNF4 is a SUMO-targeted E3 ubiquitin-protein ligase with a pivotal function in the DNA damage response (DDR) through interacting with the deubiquitinating enzyme ubiquitin-specific protease 11 (USP11), a known DDR-component, and further facilitating DNA repair []. It plays a novel role in preventing the loss of intact chromosomes and ensures the maintenance of chromosome integrity. Moreover, RNF4 is responsible for the UbcH5A-catalyzed formation of K48 chains that target SUMO-modified promyelocytic leukemia (PML) protein for proteasomal degradation in response to arsenic treatment []. It also interacts with telomeric repeat binding factor 2 (TRF2) in a small ubiquitin-like modifiers (SUMO)-dependent manner and preferentially targets SUMO-conjugated TRF2 for ubiquitination through SUMO-interacting motifs (SIMs) []. Furthermore, RNF4 can form a complex with a Ubc13-ubiquitin conjugate and Ube2V2. It catalyzes K63-linked polyubiquitination by the Ube2V2-Ubc13 (ubiquitin-loaded) complex []. Meanwhile, RNF4 negatively regulates nuclear factor kappa B (NF-kappaB) signaling by down-regulating transforming growth factor beta (TGF-beta)-activated kinase 1 (TAK1)-TAK1-binding protein2 (TAB2) []. RNF4 contains four SIMs followed by a C3HC4-type RING-HC finger at the C-terminal [].This entry represents the C3HC4-type RING-HC finger.
MDM2 is an E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome []. p53 acts as an important defense mechanism against cancer, and is negatively regulated by interaction with the oncoprotein MDM2 []. MDM2 overexpression correlates with metastasis and advanced forms of several cancers and may be used as a cancer drug target []. In addition, MDM2 has important roles in the cell independent of p53. It interacts with several proteins such as Rb/E2F-1 complex [], the DNA methyltransferase DNMT3A [], p107 [], MTBP []and the cyclin kinase inhibitor p21 []. MDM2 also affects cell apoptosis [, ].MDM2 contains an N-terminal p53-binding domain, and a C-terminal modified C2H2C4-type RING-HC finger conferring E3 ligase activity that is required for ubiquitination and nuclear export of p53. It is also responsible for the hetero-oligomerization of MDM2, which is crucial for the suppression of P53 activity during embryonic development, and the recruitment of E2 ubiquitin-conjugating enzymes []. MDM2 also harbours a RanBP2-type zinc finger (Znf-RanBP2) domain, as well as a nuclear localisation signal (NLS) and a nuclear export signal (NES), near the central acidic region. The Znf-RanBP2 domain plays an important role in mediating MDM2 binding to ribosomal proteins and thus is involved in MDM2-mediated p53 suppression.This entry represents the C-terminal modified C2H2C4-type RING-HC finger.
RING1 is a transcriptional repressor associated with the Polycomb group (PcG) protein complex involved in stable repression of gene activity. It is a core component of polycomb repressive complex 1 (PRC1) that functions as an E3-ubuiquitin ligase that transferring the mono-ubuiquitin mark to the C-terminal tail of Histone H2A at K118/K119 []. PRC1 is also capable of chromatin compaction, a function not requiring histone tails, and this activity appears important in gene silencing []. RING1 interacts with multiple PcG proteins and displays tumorigenic activity[]. It also shows zinc-dependent DNA binding activity. Moreover, RING1 inhibits transactivation of the DNA-binding protein recombination signal binding protein-Jkappa (RBP-J) by Notch through interaction with the LIM domains of KyoT2 []. RING1 contains a C3HC4-type RING-HC finger [].
NOT4, also known as CCR4-associated factor 4, E3 ubiquitin-protein ligase CNOT4, or potential transcriptional repressor NOT4, is a component of the multifunctional CCR4-NOT complex, a global regulator of RNA polymerase II transcription. It associates with polysomes and contributes to the negative regulation of protein synthesis [, , , , , , , ]. NOT4 functions as an E3 ubiquitin-protein ligase that interacts with a specific E2, Ubc4/5 in yeast, and the orthologue UbcH5B in humans, and ubiquitylates a wide range of substrates, including ribosome-associated factors []. Thus, it plays a role in cotranslational quality control (QC) through ribosome-associated ubiquitination and degradation of aberrant peptides. NOT4 contains a C4C4-type RING finger motif, whose overall folding is similar to that of the C3HC4-type RING-HC finger, a central RNA recognition motif (RRM), and a C-terminal domain predicted to be unstructured [].
Tripartite motif-containing protein 63 (TRIM63), also known as MURF-1 is an E3 ubiquitin-protein ligase involved in ubiquitin-mediated muscle protein turnover [, ]. It is predominantly fast (type II) fibre-associated in skeletal muscle and can bind to many myofibrillar proteins, including titin, nebulin, the nebulin-related protein NRAP, troponin-I (TnI), troponin-T (TnT), myosin light chain 2 (MLC-2), myotilin, and T-cap. The early and robust upregulation of MuRF-1 is triggered by disuse, denervation, starvation, sepsis, or steroid administration resulting in skeletal muscle atrophy. It also plays a role in maintaining titin M-line integrity []. It associates with the periphery of the M-line lattice and may be involved in the regulation of the titin kinase domain []. It also participates in muscle stress response pathways and gene expression [, ]. MuRF-1 belongs to the C-II subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox2, and a coiled coil region, as well as a COS (carboxyl-terminal subgroup one signature) box, and an acidic residue-rich (AR) domain. It also harbours a MURF family-specific conserved box (MFC) between its RING-HC finger and Bbox domains [].This entry represents the C3HC4-type RING-HC finger found in TRIM63.
TRIM68 is an E3 ubiquitin-protein ligase that negatively regulates Toll-like receptor (TLR)- and RIG-I-like receptor (RLR)-driven type I interferon production by degrading TRK fused gene (TFG), a novel driver of IFN-beta downstream of anti-viral detection systems []. It also functions as a cofactor for androgen receptor-mediated transcription through regulating ligand-dependent transcription of androgen receptor in prostate cancer cells []. Moreover, TRIM68 is a cellular target of autoantibody responses in Sjogren"s syndrome (SS), as well as systemic lupus erythematosus (SLE). It is also an auto-antigen for T cells in SS and SLE [, ]. TRIM68 belongs the C-IV subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, a B-box, and two coiled coil domains, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain. This entry represents the C3HC4-type RING-HC finger found in TRIM68.
TRIM58, also known as protein BIA2, is an erythroid E3 ubiquitin-protein ligase induced during late erythropoiesis. It binds and ubiquitinates the intermediate chain of the microtubule motor dynein (DYNC1LI1/DYNC1LI2), stimulating the degradation of the dynein holoprotein complex. It may participate in the erythroblast enucleation process through regulation of nuclear polarization. TRIM58 belongs to the C-IV subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain [].
RNF114 (also known as Znf313) is a p21(WAF1)-targeting ubiquitin E3 ligase that interacts with X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) and may play a role in p53-mediated cell-fate decisions [, ]. It is involved in immune response to double-stranded RNA in disease pathogenesis []. Moreover, RNF114 interacts with A20 and modulates its ubiquitination []. It negatively regulates nuclear factor-kappaB (NF-kappaB)-dependent transcription and positively regulates T-cell activation []. RNF114 may play a putative role in the regulation of immune responses, since it corresponds to a novel psoriasis susceptibility gene, ZNF313 []. RNF114, together with three closely related proteins: RNF125, RNF138 and RNF166, forms a novel family of ubiquitin ligases with a C3HC4-type RING-HC finger, a C2HC-, and two C2H2-type zinc fingers, as well as a ubiquitin interacting motif (UIM).
Cbl-b, also known as RNF56, has been identified as a regulator of antigen-specific, T cell-intrinsic, peripheral immune tolerance, a state also known as clonal anergy. It may inhibit activation of the p85 subunit of phosphoinositide 3-kinase (PI3K), protein kinase C-theta (PKC-theta) []and negatively regulates T-cell receptor-induced transcription factor nuclear factor kappaB (NF-kappaB) activation []. In addition, Cbl-b may target multiple signaling molecules involved in transforming growth factor (TGF)-beta-mediated transactivation pathways []. Cbl-b contains a tyrosine-kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, is composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a proline rich domain, a nuclear localization signal, a C3HC4-type RING-HC finger and an ubiquitin-associated (UBA) domain []. This entry represents the C3HC4-type RING-HC finger.
The lipocalin family can be subdivided into kernal and outlier sets. The kernal lipocalins form the largest self consistent group, comprising the subfamily of alpha-1-microglobulins. The outlier lipocalins form several smaller distinct subgroups: the OBPs, the von Ebner's gland proteins, alpha-1-acid glycoproteins, tick histamine binding proteins and the nitrophorins.Alpha-1-microglobulin (A1M), also known as protein HC (for Heterogeneous Charge), is a low molecular weight protein component of plasma first discovered in pathological human urine. It is a member of the lipocalin superfamily. Although much is now known of its structure and properties, the function and physiological role of A1M remains unclear, although evidence suggests that it functions in the regulation of the immune system. A1M is known to exist in both a free form and complexed to other macromolecules: immunoglobulin A (IgA) in humans and alpha-1-inhibitor-3 in the rat. Free A1M is a monomeric protein composed of one 188 residue polypeptide and contains three cysteines, two of which (residues 75 and 173) form a conserved intra-molecular disulphide link []. A1M is glycosylated by three separate carbohydrate chains: two complex carbohydrates are N-linked to asparagines at residues 17 and 96, and the other simple carbohydrate is O-linked to threonine at position 5. 22% of the total molecular mass of the protein is derived from carbohydrate. Free A1M is extremely heterogeneous in charge, and is found tightly associated with a chromophore. This chromophoric group is covalently bound to the free cysteine residue at position 34. It also binds retinol as a major ligand, but this is probably distinct from the its covalent chromophore. The glycosylation is different between species. The principal sites of A1M synthesis are the liver and kidney. Half of all human plasma A1M (about 0.03mg/ml) forms a 1:1 complex with about 5% of plasma immunoglobulin A. The resulting macromolecular complex has a molecular weight of 200000, anda plasma concentration of 0.3mg/ml. It can exhibit both antibody activity and affect many of the biological actions of free A1M []. A1M has many affects on the immune system. It inhibits stimulation of cultured lymphocytes by protein antigens; it can induce cell division of lymphocytes, a mitogenic effect that can either be enhanced or inhibited by the action of other plasma components; it inhibits neutrophil granulocyte migration in vitro; and it inhibits chemotaxis.
