Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF3 subfamily, TRAF domain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF3 was first described as a molecule that binds the cytoplasmic tail of CD40. However, it is not required for CD40 signaling. More recently, TRAF3 has been identified as a key regulator of type I interferon (IFN) production and the mammalian innate antiviral immunity. It mediates IFN responses in Toll-like receptor (TLR)-dependent as well as TLR-independent viral recognition pathways. It is also a key element in immunological homeostasis through its regulation of the anti-inflammatory cytokine interleukin-10. TRAF3 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 353 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 432
Cdd:cd03777   1 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 433 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 512
Cdd:cd03777  81 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 160

                       170       180
                ....*....|....*....|....*.
gi 22027620 513 VAQTVLENGTYIKDDTIFIKVIVDTS 538
Cdd:cd03777 161 VAQTVLENGTYIKDDTIFIKVIVDTS 186

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 22027620   136 HLKNdCHFEELPCVRPDCKEKVLRKDLRDHVEKACKYREATCSH----CKSQVPMIALQKH 192
Cdd:pfam02176   1 HLET-CPFFPIPCPNGCCKKKILREDLPDHLELDCPKAEVPCPFkvfgCKEDVKREALQRH 60

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF3 subfamily, TRAF domain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF3 was first described as a molecule that binds the cytoplasmic tail of CD40. However, it is not required for CD40 signaling. More recently, TRAF3 has been identified as a key regulator of type I interferon (IFN) production and the mammalian innate antiviral immunity. It mediates IFN responses in Toll-like receptor (TLR)-dependent as well as TLR-independent viral recognition pathways. It is also a key element in immunological homeostasis through its regulation of the anti-inflammatory cytokine interleukin-10. TRAF3 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 353 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 432
Cdd:cd03777   1 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 433 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 512
Cdd:cd03777  81 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 160

                       170       180
                ....*....|....*....|....*.
gi 22027620 513 VAQTVLENGTYIKDDTIFIKVIVDTS 538
Cdd:cd03777 161 VAQTVLENGTYIKDDTIFIKVIVDTS 186

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 22027620   136 HLKNdCHFEELPCVRPDCKEKVLRKDLRDHVEKACKYREATCSH----CKSQVPMIALQKH 192
Cdd:pfam02176   1 HLET-CPFFPIPCPNGCCKKKILREDLPDHLELDCPKAEVPCPFkvfgCKEDVKREALQRH 60

helix-rich Mycoplasma protein; Members of this family occur strictly within a subset of Mycoplasma species. Members average 750 amino acids in length, including signal peptide. Sequences are predicted (Jpred 3) to be almost entirely alpha-helical. These sequences show strong periodicity (consistent with long alpha helical structures) and low complexity rich in D,E,N,Q, and K. Genes encoding these proteins are often found in tandem. The function is unknown.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620   214 LRSEGTNQQIKAHEASSAV----QHVNLLKEWSNSLEKKVSLLQNESVEKNKSIQSLHNQICSFEIEIERQKEMLRNNES 289
Cdd:TIGR04523 312 LKSELKNQEKKLEEIQNQIsqnnKIISQLNEQISQLKKELTNSESENSEKQRELEEKQNEIEKLKKENQSYKQEIKNLES 391

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 22027620   290 KILHLQRVIDSQAEKLKELDKEIRPFRQNWE----EADSMKSSVESLQNRVTELESVD 343
Cdd:TIGR04523 392 QINDLESKIQNQEKLNQQKDEQIKKLQQEKEllekEIERLKETIIKNNSEIKDLTNQD 449

Chromosome segregation protein NDC80, interacts with SMC proteins [Cell cycle control, cell division, chromosome partitioning];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 220 NQQIKAHEASSAVQHVNLLKEWSNSLEKKVSLLQ---NESVEKN---KSIQSLHNQICSFEI--EIERQKemlRNNESKI 291
Cdd:COG5185 262 NTDLRLEKLGENAESSKRLNENANNLIKQFENTKekiAEYTKSIdikKATESLEEQLAAAEAeqELEESK---RETETGI 338

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 292 LHLQRVIDSQAEKLKELDKEIRP----------FRQNWEEADSMKSSVESL-----QNRVTELESVDKSAGQVARNTGLL 356
Cdd:COG5185 339 QNLTAEIEQGQESLTENLEAIKEeienivgeveLSKSSEELDSFKDTIESTkesldEIPQNQRGYAQEILATLEDTLKAA 418

                ....*..
gi 22027620 357 ESQLSRH 363
Cdd:COG5185 419 DRQIEEL 425

Zinc finger, C3HC4 type (RING finger); The C3HC4 type zinc-finger (RING finger) is a cysteine-rich domain of 40 to 60 residues that coordinates two zinc ions, and has the consensus sequence: C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C where X is any amino acid. Many proteins containing a RING finger play a key role in the ubiquitination pathway.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 22027620    56 CHLVLCSPKQ----TECGHRFCESCMAALLSSSSPKCTAC 91
Cdd:pfam00097   1 CPICLEEPKDpvtlLPCGHLFCSKCIRSWLESGNVTCPLC 40

DNA repair protein rad18; All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 22027620    44 VKTVEDKYKCEKCHLVLCSPKQTECGHRFCESCMAALLsSSSPKCTAC----QESIVK 97
Cdd:TIGR00599  20 LYPLDTSLRCHICKDFFDVPVLTSCSHTFCSLCIRRCL-SNQPKCPLCraedQESKLR 76

family of the cytolysin A (ClyA) family alpha pore-forming toxins (alpha-PFT) including Bacillus cereus HblB, Aeromonas hydrophila AhlB, Bacillus thuringiensis Cry6Aa and similar proteins; This family belongs to the ClyA family of alpha-PFT bacterial toxins. PFTs form the major group of virulence factors in many pathogenic bacteria and in general are critical components of the molecular offensive and defensive machinery of cells in all kingdoms of life. Bacterial PFTs facilitate the takeover of host resources by puncturing holes in the membrane. PFTs can be classified as alpha-PFTs and beta-PFTs depending on the secondary structures of their membrane component. Alpha-PFTs use a ring of amphipathic helices while beta-PFTs use a beta-barrel to construct the pore. Members of this family include the toxins: Bacillus cereus hemolysin binding component B (HblB or HBL-B) of the diarrheal enterotoxin hemolysin BL, Aeromonas hydrophila hemolytic (Ahl) component B (AhlB) of the tripartite AhlABC toxin, Vibrio cholerae cytotoxin motility associated killing factor A (MakA) cytotoxin, Xenorhabdus nematophila alpha-xenorhabdolysin (XaxA), Bacillus thuringiensis crystal 6Aa (Cry6Aa) parasporal crystal (Cry) toxin, and Bacillus cereus non-hemolytic enterotoxin (Nhe) component A (NheA) of the non-hemolytic enterotoxin Nhe, which, despite its name, is hemolytic, among others. In solution, ClyA proteins have an elongated, almost entirely alpha-helical structure, except for a short hydrophobic beta-hairpin known as the beta-tongue. Pore formation by ClyA requires circular oligomerization of the toxin by a sequential mechanism. This, in turn, concentrates the amphipathic helices in the center of the ring-like structure, forming a helical barrel that inserts into the membrane by a wedge-like mechanism. Compared with ClyA, NheA is almost entirely alpha-helical with an enlarged "head" domain, and an enlarged beta-tongue; it has been proposed that NheA could even form beta-barrel pores. Alpha-PFTs with similar structures are increasingly being found in eukaryotes, in particular as components of the immune systems of animals. This family may be distantly related to Escherichia coli alpha-PFT hemolysin E (HlyE, also known as ClyA or SheA).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 239 KEWSNSLEKKVSLLQNESVEKNKSIQSLHNQICSFEIEIERQKEMLRNNESKILH-LQRVIDSQAEKLKELDKEIRPFRQ 317
Cdd:cd21116  47 LEWLNEIKPKLLSLPNDIIGYNNTFQSYYPDLIELADNLIKGDQGAKQQLLQGLEaLQSQVTKKQTSVTSFINELTTFKN 126

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
gi 22027620 318 NWEE-ADSMKSSVESLQNRVTELESVDKSAGQVARNTGLLESQLSRHDQMLSV 369
Cdd:cd21116 127 DLDDdSRNLQTDATKAQAQVAVLNALKNQLNSLAEQIDAAIDALEKLSNDWQT 179

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF3 subfamily, TRAF domain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF3 was first described as a molecule that binds the cytoplasmic tail of CD40. However, it is not required for CD40 signaling. More recently, TRAF3 has been identified as a key regulator of type I interferon (IFN) production and the mammalian innate antiviral immunity. It mediates IFN responses in Toll-like receptor (TLR)-dependent as well as TLR-independent viral recognition pathways. It is also a key element in immunological homeostasis through its regulation of the anti-inflammatory cytokine interleukin-10. TRAF3 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 353 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 432
Cdd:cd03777   1 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 433 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 512
Cdd:cd03777  81 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 160

                       170       180
                ....*....|....*....|....*.
gi 22027620 513 VAQTVLENGTYIKDDTIFIKVIVDTS 538
Cdd:cd03777 161 VAQTVLENGTYIKDDTIFIKVIVDTS 186

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF5 subfamily, TRAF domain, C-terminal MATH subdomain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF5 was identified as an activator of nuclear factor-kappaB and a regulator of lymphotoxin-beta receptor and CD40 signaling. Its interaction with CD40 is indirect, involving hetero-oligomerization with TRAF3. In addition, TRAF5 has been shown to associate with other TNFRs including CD27, CD30, OX40 and GITR (glucocorticoid-induced TNFR). It plays a role in modulating Th2 immune responses (driven by OX40 costimulation) and T-cell activation (triggered by GITR). It is also involved in osteoclastogenesis. TRAF5 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 391 GVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCARVYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVT 470
Cdd:cd03780   1 GKLIWKVTDYKMKKKEAVDGHTVSIFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVT 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 22027620 471 LMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVFVAQTVLENG--TYIKDDTIFIKVIVD 536
Cdd:cd03780  81 LMLLDQSGKKNHIMETFKADPNSSSFKRPDGEMNIASGCPRFVAHSVLENAknTYIKDDTLFLKVAVD 148

Tumor Necrosis Factor Receptor (TNFR) Associated Factor (TRAF) family, TRAF1 subfamily, TRAF domain, C-terminal MATH subdomain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF1 expression is the most restricted among the TRAFs. It is found exclusively in activated lymphocytes, dendritic cells and certain epithelia. TRAF1 associates, directly or indirectly through heterodimerization with TRAF2, with the TNFR family receptors TNFR-2, CD30, RANK, CD40 and LMP1, among others. It also binds the intracellular proteins TRADD, TANK, TRIP, RIP1, RIP2 and FLIP. TRAF1 is unique among the TRAFs in that it lacks a RING domain, which is critical for the activation of nuclear factor-kappaB and Jun NH2-terminal kinase. Studies on TRAF1-deficient mice suggest that TRAF1 has a negative regulatory role in TNFR-mediated signaling events. TRAF1 contains one zinc finger and one TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 391 GVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCARVYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVT 470
Cdd:cd03779   1 GTFLWKITDVSQKQRESSHGRDVSLCSPAFYTAKYGYKVCLRLYLNGDGAGKGTHISLFFVIMKGEYDALLPWPFRHKVT 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 22027620 471 LMLMDQgSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVFVAQTVLEN--GTYIKDDTIFIKVIVD 536
Cdd:cd03779  81 FMLLDQ-NNREHVIDAFRPDLSSASFQRPVSDMNVASGCPLFFPLKKLQSpkHAYCKDDTIYIKCVVD 147

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF6 subfamily, TRAF domain, C-terminal MATH subdomain; composed of proteins with similarity to human TRAF6, including the Drosophila protein DTRAF2. TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF6 is the most divergent in its TRAF domain among the mammalian TRAFs. In addition to mediating TNFR family signaling, it is also an essential signaling molecule of the interleukin-1/Toll-like receptor superfamily. Whereas other TRAF molecules display similar and overlapping TNFR-binding specificities, TRAF6 binds completely different sites on receptors such as CD40 and RANK. TRAF6 serves as a molecular bridge between innate and adaptive immunity and plays a central role in osteoimmunology. DTRAF2, as an activator of nuclear factor-kappaB, plays a pivotal role in Drosophila development and innate immunity. TRAF6 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 391 GVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCARVYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVT 470
Cdd:cd03776   1 GIYVWKIKNFSNLRRSMEAGSPVVIHSPGFYTSPPGYKLCARLNLSLPEARCPNYISLFVHLMQGENDSHLDWPFQGTIT 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 22027620 471 LMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIAS-GCPVFVAQTVLENGTYIKDDTIFIKVIV 535
Cdd:cd03776  81 LTLLDQSEPRQNIHETMMSKPELLAFQRPTTDRNPKGfGYVEFAHIEDLLQRGFVKNDTLLIKIEV 146

MATH (meprin and TRAF-C homology) domain; an independent folding unit with an eight-stranded beta-sandwich structure found in meprins, TRAFs and other proteins. Meprins comprise a class of extracellular metalloproteases which are anchored to the membrane and are capable of cleaving growth factors, extracellular matrix proteins, and biologically active peptides. TRAF molecules serve as adapter proteins that link cell surface receptors of the Tumor Necrosis Factor and 1nterleukin-1/Toll-like families to downstream kinase cascades, which results in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses in the immune and inflammatory systems. Other members include the ubiquitin ligases, TRIM37 and SPOP, and the ubiquitin-specific proteases, HAUSP and Ubp21p. A large number of uncharacterized members mostly from lineage-specific expansions in C. elegans and rice contain MATH and BTB domains, similar to SPOP. The MATH domain has been shown to bind peptide/protein substrates in TRAFs and HAUSP. It is possible that the MATH domain in other members of this superfamily also interacts with various protein substrates. The TRAF domain may also be involved in the trimerization of TRAFs. Based on homology, it is postulated that the MATH domain in meprins may be involved in its tetramer assembly and that the MATH domain, in general, may take part in diverse modular arrangements defined by adjacent multimerization domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 391 GVLIWKIRDYKRRKQEavmgktlSLYSQPFYTGyfGYKMCARVYLNGDGmGKGTHLSLFFVIMRGEYDaLLPWPFKQKVT 470
Cdd:cd00121   1 GKHTWKIVNFSELEGE-------SIYSPPFEVG--GYKWRIRIYPNGDG-ESGDYLSLYLELDKGESD-LEKWSVRAEFT 69

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 22027620 471 LMLMDQgSSRRHLGDAFKPDPNSssfkkptgEMNIASGCPVFVAQTVLENGTYIKDDTIFIKVIVD 536
Cdd:cd00121  70 LKLVNQ-NGGKSLSKSFTHVFFS--------EKGSGWGFPKFISWDDLEDSYYLVDDSLTIEVEVK 126

Modified RING finger, HC subclass (C3HC3D-type), found in tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) and similar proteins; TRAF5, also known as RING finger protein 84 (RNF84), is an important signal transducer for a wide range of TNF receptor superfamily members, including tumor necrosis factor receptor 1 (TNFR1), TNFR2, CD40, and other lymphocyte costimulatory receptors, RANK/TRANCE-R, ectodysplasin-A Receptor (EDAR), lymphotoxin-beta receptor (LT-betaR), latent membrane protein 1 (LMP1), and IRE1. It functions as an activator of NF-kappaB, MAPK, and JNK, and is involved in both RANKL- and TNFalpha-induced osteoclastogenesis. It mediates CD40 signaling by associating with the cytoplasmic tail of CD40. It also negatively regulates Toll-like receptor (TLR) signaling and functions as a negative regulator of the interleukin 6 (IL-6) receptor signaling pathway that limits the differentiation of inflammatory CD4(+) T cells. TRAF5 contains an N-terminal domain with a modified C3HC3D-type RING-HC finger and several zinc fingers, and a C-terminal TRAF domain that comprises a coiled coil domain and a conserved TRAF-C domain.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 22027620  48 EDKYKCEKCHLVLCSPKQTECGHRFCESCMAALLS-SSSPKCTACQESIVKDKVF 101
Cdd:cd16642   2 EDRYKCATCHFVLHNPHQTGCGHRFCQHCILSLLElNTTPICPIDKETIKSDEVF 56

meprin and TRAF homology;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620    392 VLIWKIRDYKRrkqeavMGKTLSLYSQPFYTgyFGYKMCARVYLNGDgmgkgtHLSLFFVIMRGEYDALlPWPFKQKVTL 471
Cdd:smart00061   1 VLSHTFKNVSR------LEEGESYFSPSEEH--FNIPWRLKIYRKNG------FLSLYLHCEKEECDSR-KWSIEAEFTL 65

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|..
gi 22027620    472 MLMDQGSSRRhlgdafkPDPNSSSFKKPTGemniaSGCPVFV 513
Cdd:smart00061  66 KLVSQNGKSL-------SKKDKHVFEKPSG-----WGFSKFI 95

RING finger, HC subclass, found in tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and similar proteins; TRAF2, also known as tumor necrosis factor type 2 receptor-associated protein 3, is an E3 ubiquitin-protein ligase that was identified as a 75 kDa tumor necrosis factor receptor (TNF-R2)-associated signaling protein. It interacts with members of the TNF receptor superfamily and connects the receptors to downstream signaling proteins. It also mediates K63-linked polyubiquitination of RIP1, a kinase pivotal in TNFalpha-induced NF-kappaB activation. Moreover, TRAF2 regulates peripheral CD8(+) T-cell and NKT-cell homeostasis by modulating sensitivity to IL-15. It also acts as an important biological suppressor of necroptosis. It inhibits TNF-related apoptosis inducing ligand (TRAIL)- and CD95L-induced apoptosis and necroptosis. TRAF2 contains an N-terminal domain with a typical C3HC4-type RING-HC finger and several zinc fingers, and a C-terminal TRAF domain that comprises a coiled coil domain and a conserved TRAF-C domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 22027620  50 KYKCEKCHLVLCSPKQTECGHRFCESCMAALLSSSSPKCTAC 91
Cdd:cd16639   1 KYLCSDCRNILRRPFQAQCGHRYCSYCLKKILSSGPQKCAAC 42

RING finger, HC subclass, found in tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1)-like and similar proteins; TRAF1, also known as Epstein-Barr virus-induced protein 6 (EBI6), is an adapter molecule that regulates the activation of NF-kappa-B and JNK. It plays a role in the regulation of cell survival and apoptosis. The heterotrimer formed by TRAF1 and TRAF2 is part of an E3 ubiquitin-protein ligase complex that promotes ubiquitination of target proteins, such as MAP3K14. The TRAF1/TRAF2 complex recruits the antiapoptotic E3 protein-ubiquitin ligases BIRC2 and BIRC3 to TNFRSF1B/TNFR2. This subfamily corresponds a group of TRAF1-like proteins that contains an N-terminal domain with a typical C3HC4-type RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 22027620  48 EDKYKCEKCHLVLCSPKQTECGHRFCESCMAALL-SSSSPKCTACQE 93
Cdd:cd23125   2 EEKYLCCNCKNVLKKAQQTLCGHRYCLACLSWIVrNNKNPICQKCKE 48

Meprin family, Beta subunit, MATH domain; Meprins are multidomain extracellular metalloproteases capable of cleaving growth factors, cytokines, extracellular matrix proteins, and biologically active peptides. They are composed of two related subunits, alpha and beta, which form homo- or hetro-complexes where the basic unit is a disulfide-linked dimer. The beta subunit is a type I membrane protein, which forms homodimers or heterotetramers (alpha2beta2 or alpha3beta). Meprin beta shows preference for acidic residues at the P1 and P1' sites of its substrate. Among its best substrates are growth factors and chemokines such as gastrin and osteopontin. Both alpha and beta subunits contain a catalytic astacin (M12 family) protease domain followed by the adhesion or interaction domains MAM, MATH and AM. The MATH and MAM domains provide symmetrical intersubunit disulfide bonds necessary for the dimerization of meprin subunits. The MATH domain may also be required for folding of an activable zymogen.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 394 IWKIRDYKRrkqeaVMGKTL---SLYSQPFYTGYfGYKMCARVYLNGDGMGKGtHLSLFFVIMRGEYDALLPWPFK-QKV 469
Cdd:cd03782   5 IWHIRNFTQ-----LLATTPpngKIYSPPFLSST-GYSFQVGLYLNGTDDYPG-NLAIYLHLTSGPNDDQLQWPCPwQQA 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 470 TLMLMDQGSS-RRHLG-------DAFK--------------------PDPNSSSFKKPTGemniaSGCPVFVAQTVLENG 521
Cdd:cd03782  78 TMMLLDQHPDiRQRMSnqrsvttDPNMtstdsdeyfwddprkvgsevTDTDGSTFYRGPG-----YGTSAFITHLRLRSR 152

                       170
                ....*....|
gi 22027620 522 TYIKDDTIFI 531
Cdd:cd03782 153 DFIKGDDVIF 162

Modified RING finger, HC subclass (C3HC3D-type), found in uncharacterized proteins similar to tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4); This subfamily corresponds to a group of uncharacterized proteins that shows high sequence similarity with tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4). TRAF4, also known as cysteine-rich domain associated with RING and Traf domains protein 1, or metastatic lymph node gene 62 protein (MLN 62), or RING finger protein 83 (RNF83), is a member of TRAF protein family, which mainly function in the immune system, where they mediate signaling through tumor necrosis factor receptors (TNFRs) and interleukin-1/Toll-like receptors (IL-1/TLRs). It also plays a critical role in the nervous system, as well as in carcinogenesis. Like TRAF4, members of this subfamily contain a modified C3HC3D-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 22027620  47 VEDKYKCEKCHLVLCSPKQ-TECGHRFCESCMAALLsSSSPKCTACQESIVKD 98
Cdd:cd23126   1 LDKKYECPVCCQVLRYPVQfEECGHRVCSSCLPELL-RVEPRCPIDQGPIDRD 52

Chromosome segregation protein NDC80, interacts with SMC proteins [Cell cycle control, cell division, chromosome partitioning];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 220 NQQIKAHEASSAVQHVNLLKEWSNSLEKKVSLLQ---NESVEKN---KSIQSLHNQICSFEI--EIERQKemlRNNESKI 291
Cdd:COG5185 262 NTDLRLEKLGENAESSKRLNENANNLIKQFENTKekiAEYTKSIdikKATESLEEQLAAAEAeqELEESK---RETETGI 338

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 292 LHLQRVIDSQAEKLKELDKEIRP----------FRQNWEEADSMKSSVESL-----QNRVTELESVDKSAGQVARNTGLL 356
Cdd:COG5185 339 QNLTAEIEQGQESLTENLEAIKEeienivgeveLSKSSEELDSFKDTIESTkesldEIPQNQRGYAQEILATLEDTLKAA 418

                ....*..
gi 22027620 357 ESQLSRH 363
Cdd:COG5185 419 DRQIEEL 425

helix-rich Mycoplasma protein; Members of this family occur strictly within a subset of Mycoplasma species. Members average 750 amino acids in length, including signal peptide. Sequences are predicted (Jpred 3) to be almost entirely alpha-helical. These sequences show strong periodicity (consistent with long alpha helical structures) and low complexity rich in D,E,N,Q, and K. Genes encoding these proteins are often found in tandem. The function is unknown.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620   235 VNLLKEWSNSLEKKVSLLQNESVEKNKSIQSLHNQICSFEIEIERQKEMLRNNESKILHLQRVIDSQAEKLKELDKEIRP 314
Cdd:TIGR04523 220 ISELKKQNNQLKDNIEKKQQEINEKTTEISNTQTQLNQLKDEQNKIKKQLSEKQKELEQNNKKIKELEKQLNQLKSEISD 299

                          90       100       110
                  ....*....|....*....|....*....|.
gi 22027620   315 FR----QNWEEadSMKSSVESLQNRVTELES 341
Cdd:TIGR04523 300 LNnqkeQDWNK--ELKSELKNQEKKLEEIQN 328

RING finger, HC subclass, found in radiation sensitivity protein 5 (RAD5) and similar proteins; RAD5, also known as revertibility protein 2 (REV2), or DNA repair protein RAD5, is a probable helicase, and a member of the UBC2/RAD6 epistasis group. It functions with the DNA repair protein RAD18 in error-free postreplication DNA repair. It is involved in the maintenance of wild-type rates of instability of simple repetitive sequences such as poly(GT) repeats. It may also be involved in maintaining a balance which acts in favor of error-prone non-homologous joining during DNA double-strand breaks repairs. It recruits the UBC13-MMS2 dimer to chromatin for DNA repair. RAD5 contains a typical C3HC4-type RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 22027620  66 TECGHRFCESCMAALL-----SSSSPKCTACQESIVKDKVFK 102
Cdd:cd23131  22 TECGHSFCEDCLLEYIefqnkKKLDLKCPNCREPISKYRLLK 63

helix-rich Mycoplasma protein; Members of this family occur strictly within a subset of Mycoplasma species. Members average 750 amino acids in length, including signal peptide. Sequences are predicted (Jpred 3) to be almost entirely alpha-helical. These sequences show strong periodicity (consistent with long alpha helical structures) and low complexity rich in D,E,N,Q, and K. Genes encoding these proteins are often found in tandem. The function is unknown.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620   236 NLLKEWSNSLEKKVSLLQNESVEKNKSIQSLHNQICSfeieIERQKEMLRNNESKIlhlQRVIdsqAEKLKELDKEIRpf 315
Cdd:TIGR04523 310 KELKSELKNQEKKLEEIQNQISQNNKIISQLNEQISQ----LKKELTNSESENSEK---QREL---EEKQNEIEKLKK-- 377

                          90       100
                  ....*....|....*....|....*.
gi 22027620   316 rqnweEADSMKSSVESLQNRVTELES 341
Cdd:TIGR04523 378 -----ENQSYKQEIKNLESQINDLES 398

Uncharacterized conserved protein, contains RING Zn-finger [General function prediction only];

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 22027620  52 KCEKCHLVLCSPKQTE-CGHRFCESCMAALLSSSSPKCTACQ-ESIVKDKVFKDNCCKREI 110
Cdd:COG5222 276 KCPLCHCLLRNPMKTPcCGHTFCDECIGTALLDSDFKCPNCSrKDVLLDGLTPDIDKKLEV 336

Modified RING finger, HC subclass (C3HC3D-type), found in tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) and similar proteins; TRAF4, also known as cysteine-rich domain associated with RING and Traf domains protein 1, metastatic lymph node gene 62 protein (MLN 62), or RING finger protein 83 (RNF83), is a member of the TRAF protein family, which mainly function in the immune system, where they mediate signaling through tumor necrosis factor receptors (TNFRs) and interleukin-1/Toll-like receptors (IL-1/TLRs). It also plays a critical role in nervous system, as well as in carcinogenesis. TRAF4 promotes the growth and invasion of colon cancer through the Wnt/beta-catenin pathway. It contributes to the TNFalpha-induced activation of the 70 kDa ribosomal protein S6 kinase (p70s6k) signaling pathway, and activation of transforming growth factor beta (TGF-beta)-induced SMAD-dependent signaling and non-SMAD signaling in breast cancer. It also enhances osteosarcoma cell proliferation and invasion by the Akt signaling pathway. Moreover, TRAF4 is a novel phosphoinositide-binding protein modulating tight junctions and favoring cell migration. TRAF4 contains an N-terminal domain with a modified C3HC3D-type RING-HC finger and several zinc fingers, and a C-terminal TRAF domain that comprises a coiled coil domain and a conserved TRAF-C domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 22027620  50 KYKCEKCHLVLCSPKQ-TECGHRFCESCMAALLSSSSPKC 88
Cdd:cd16641   1 RLLCPLCRLPMREPVQiSTCGHRFCDTCLQEFLSEGVFKC 40

Uncharacterized conserved protein YhaN, contains AAA domain [Function unknown];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 221 QQIKahEASSAVQHVNLLKEWSNSLEKKVSLLQNESVEKNKSIQSLHNQICSFEIEIERQKemlrnneskilhLQRVIDS 300
Cdd:COG4717  78 EELK--EAEEKEEEYAELQEELEELEEELEELEAELEELREELEKLEKLLQLLPLYQELEA------------LEAELAE 143

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 301 QAEKLKELDKEIRPFRQNWEEADSMKSSVESLQNRVTELE-----SVDKSAGQVARNTGLLESQLSRHDQMLSVHDIRLA 375
Cdd:COG4717 144 LPERLEELEERLEELRELEEELEELEAELAELQEELEELLeqlslATEEELQDLAEELEELQQRLAELEEELEEAQEELE 223

                       170       180       190       200
                ....*....|....*....|....*....|....*....|
gi 22027620 376 DMDLRFQVLETASyngvliWKIRDYKRRKQEAVMGKTLSL 415
Cdd:COG4717 224 ELEEELEQLENEL------EAAALEERLKEARLLLLIAAA 257

RING finger, HC subclass, found in ligand of numb protein X 3 (LNX3); LNX3, also known as PDZ domain-containing RING finger protein 3 (PDZRN3), or Semaphorin cytoplasmic domain-associated protein 3 (SEMACAP3), is an E3 ubiquitin-protein ligase that was first identified as a Semaphorin-binding partner. It is also responsible for the ubiquitination and degradation of Numb, a component of the Notch signaling pathway that functions in the specification of cell fates during development and is known to control cell numbers during neurogenesis in vertebrates. LNX3 acts as a negative regulator of osteoblast differentiation by inhibiting Wnt-beta-catenin signaling. LNX3 also plays an important role in neuromuscular junction formation. It interacts with and ubiquitinates the muscle specific tyrosine kinase (MuSK), thus promoting its endocytosis and negatively regulating the cell surface expression of this key regulator of postsynaptic assembly. LNX3 contains an N-terminal C3HC4-type RING-HC finger, two PDZ domains, and a C-terminal LNX3 homology (LNX3H) domain.

                        10        20        30
                ....*....|....*....|....*....|.
gi 22027620  47 VEDKYKCEKCHLVLCSPKQTECGHRFCESCM 77
Cdd:cd16718   1 VDPDFKCNLCNKVLEDPLTTPCGHVFCAGCV 31

RING finger, HC subclass, found in RING finger protein 114 (RNF114) and similar proteins; RNF114, also known as zinc finger protein 228 (ZNF228) or zinc finger protein 313 (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 the immune response to double-stranded RNA in disease pathogenesis. Moreover, RNF114 interacts with A20 and modulates its ubiquitylation. 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).

                        10        20        30        40
                ....*....|....*....|....*....|....*....|...
gi 22027620  50 KYKCEKCHLVLCSPKQTECGHRFCESCMAALLSSSSPKCTACQ 92
Cdd:cd16540   1 RFTCPVCLEIFETPVRVPCGHVFCNACLQECLKPKKPVCAVCR 43

RING-finger-containing E3 ubiquitin ligase [Signal transduction mechanisms];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620  52 KCEKCHLVLCSPKQTECGHRFCESCMAALLsSSSPKCTACQESIvKDKVFKDNCCKREIL------------ALQIYCR- 118
Cdd:COG5432  27 RCRICDCRISIPCETTCGHTFCSLCIRRHL-GTQPFCPVCREDP-CESRLRGSSGSREINesharnrdllrkVLESLCRl 104

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 119 ----NESRGCAEQLMLGHllVHLKNDCHFEELPCVRPDcKEKVLRKDLRDHVEKAckyRE--ATCSHCKSQVPMIALQKH 192
Cdd:COG5432 105 prpiKEERPCRWETVIAQ--DSASGDEEWEDDLASNSS-PASIAKKTSRDSKKRK---REdlVHCPACSNLVPHNQINQH 178

                ...
gi 22027620 193 EDT 195
Cdd:COG5432 179 LDS 181

RING finger, HC subclass, found in RING finger proteins RNF113A, RNF113B, and similar proteins; RNF113A, also known as zinc finger protein 183 (ZNF183), is an E3 ubiquitin-protein ligase that physically interacts with the E2 protein, UBE2U. A nonsense mutation in RNF113A is associated with an X-linked trichothiodystrophy (TTD). Its yeast ortholog Cwc24p is predicted to have a spliceosome function and acts in a complex with Cef1p to participate in pre-U3 snoRNA splicing, indirectly affecting pre-rRNA processing. It is also important for the U2 snRNP binding to primary transcripts and co-migrates with spliceosomes. Moreover, the ortholog of RNF113A in fruit flies may also act as a spliceosome and is hypothesized to be involved in splicing, namely within the central nervous system. The ortholog in Caenorhabditis elegans is involved in DNA repair of inter-strand crosslinks. RNF113B, also known as zinc finger protein 183-like 1, shows high sequence similarity with RNF113A. Both RNF113A and RNF113B contain a CCCH-type zinc finger, which is commonly found in RNA-binding proteins involved in splicing, and a C3HC4-type RING-HC finger, which is frequently found in E3 ubiquitin ligases.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 22027620  52 KCEKCHLVLCSPKQTECGHRFCESCmAALLSSSSPKCTACQE 93
Cdd:cd16539   7 ACFICRKPFKNPVVTKCGHYFCEKC-ALKHYRKSKKCFVCGK 47

family of the cytolysin A (ClyA) family alpha pore-forming toxins (alpha-PFT) including Bacillus cereus HblB, Aeromonas hydrophila AhlB, Bacillus thuringiensis Cry6Aa and similar proteins; This family belongs to the ClyA family of alpha-PFT bacterial toxins. PFTs form the major group of virulence factors in many pathogenic bacteria and in general are critical components of the molecular offensive and defensive machinery of cells in all kingdoms of life. Bacterial PFTs facilitate the takeover of host resources by puncturing holes in the membrane. PFTs can be classified as alpha-PFTs and beta-PFTs depending on the secondary structures of their membrane component. Alpha-PFTs use a ring of amphipathic helices while beta-PFTs use a beta-barrel to construct the pore. Members of this family include the toxins: Bacillus cereus hemolysin binding component B (HblB or HBL-B) of the diarrheal enterotoxin hemolysin BL, Aeromonas hydrophila hemolytic (Ahl) component B (AhlB) of the tripartite AhlABC toxin, Vibrio cholerae cytotoxin motility associated killing factor A (MakA) cytotoxin, Xenorhabdus nematophila alpha-xenorhabdolysin (XaxA), Bacillus thuringiensis crystal 6Aa (Cry6Aa) parasporal crystal (Cry) toxin, and Bacillus cereus non-hemolytic enterotoxin (Nhe) component A (NheA) of the non-hemolytic enterotoxin Nhe, which, despite its name, is hemolytic, among others. In solution, ClyA proteins have an elongated, almost entirely alpha-helical structure, except for a short hydrophobic beta-hairpin known as the beta-tongue. Pore formation by ClyA requires circular oligomerization of the toxin by a sequential mechanism. This, in turn, concentrates the amphipathic helices in the center of the ring-like structure, forming a helical barrel that inserts into the membrane by a wedge-like mechanism. Compared with ClyA, NheA is almost entirely alpha-helical with an enlarged "head" domain, and an enlarged beta-tongue; it has been proposed that NheA could even form beta-barrel pores. Alpha-PFTs with similar structures are increasingly being found in eukaryotes, in particular as components of the immune systems of animals. This family may be distantly related to Escherichia coli alpha-PFT hemolysin E (HlyE, also known as ClyA or SheA).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22027620 239 KEWSNSLEKKVSLLQNESVEKNKSIQSLHNQICSFEIEIERQKEMLRNNESKILH-LQRVIDSQAEKLKELDKEIRPFRQ 317
Cdd:cd21116  47 LEWLNEIKPKLLSLPNDIIGYNNTFQSYYPDLIELADNLIKGDQGAKQQLLQGLEaLQSQVTKKQTSVTSFINELTTFKN 126

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
gi 22027620 318 NWEE-ADSMKSSVESLQNRVTELESVDKSAGQVARNTGLLESQLSRHDQMLSV 369
Cdd:cd21116 127 DLDDdSRNLQTDATKAQAQVAVLNALKNQLNSLAEQIDAAIDALEKLSNDWQT 179

RING finger, HC subclass, found in ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1); UHRF1, also known as inverted CCAAT box-binding protein of 90 kDa, nuclear protein 95, nuclear zinc finger protein Np95 (Np95), RING finger protein 106, transcription factor ICBP90, or E3 ubiquitin-protein ligase UHRF1, is a unique chromatin effector protein that integrates the recognition of both histone PTMs and DNA methylation. It is essential for cell proliferation and plays a critical role in the development and progression of many human carcinomas, such as laryngeal squamous cell carcinoma (LSCC), gastric cancer (GC), esophageal squamous cell carcinoma (ESCC), colorectal cancer, prostate cancer, and breast cancer. UHRF1 can acts as a transcriptional repressor through its binding to histone H3 when it is unmodified at Arg2. Its overexpression in human lung fibroblasts results in downregulation of expression of the tumor suppressor pRB. It also plays a role in transcriptional repression of the cell cycle regulator p21. Moreover, UHRF1-dependent repression of factors can facilitate the G1-S transition. It interacts with Tat-interacting protein of 60 kDa (TIP60) and induces degradation-independent ubiquitination of TIP60. It is also a N-methylpurine DNA glycosylase (MPG)-interacting protein that binds MPG in a p53 status-independent manner in the DNA base excision repair (BER) pathway. In addition, UHRF1 functions as an epigenetic regulator that is important for multiple aspects of epigenetic regulation, including maintenance of DNA methylation patterns and recognition of various histone modifications. UHRF1 contains an N-terminal ubiquitin-like domain (UBL), a tandem Tudor domain (TTD), a plant homeodomain (PHD) domain, a SET and RING finger associated (SRA) domain, and a C-terminal C3HC4-type RING-HC finger. It specifically binds to hemimethylated DNA, double-stranded CpG dinucleotides, and recruits the maintenance methyltransferase DNMT1 to its hemimethylated DNA substrate through its SRA domain. UHRF1-dependent H3K23 ubiquitylation has an essential role in maintenance DNA methylation and replication. The tandem Tudor domain directs UHRF1 binding to the heterochromatin mark histone H3K9me3 and the PHD domain targets UHRF1 to unmodified histone H3 in euchromatic regions. The RING-HC finger exhibits both autocatalytic E3 ubiquitin (Ub) ligase activity and activity against histone H3 and DNMT1.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 22027620  42 KFVKTVEDKYKCEKCHLVLCSPKQTECGHRFCESCMAALLSSSSPKCTACQESIVKDKVFKDN 104
Cdd:cd16769   4 LFLSKVEETFQCICCQELVFRPITTVCQHNVCKDCLDRSFRAQVFSCPACRYDLGRSYAMQVN 66