Tumor Necrosis Factor Receptor (TNFR) Associated Factor (TRAF) family, TRAF2 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. TRAF2 associates with the receptors TNFR-1, TNFR-2, RANK (which mediates differentiation and maturation of osteoclasts) and CD40 (which is important for the proliferation and activation of B cells), among others. It regulates distinct pathways that lead to the activation of nuclear factor-kappaB and Jun NH2-terminal kinases. TRAF2 also indirectly associates with death receptors through its interaction with TRADD (TNFR-associated death domain protein). It is involved in regulating oxidative stress or ROS-induced cell death and in the preconditioning of cells by sublethal stress for protection from subsequent injury. TRAF2 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 13277840 334 AMADLEQKVSELEVSTYDGVFIWKISDFTRKRQEAVAGRTPAIFSPAFYTSRYGYKMCLRVYLNGDGTGRGTHLSLFFVV 413
Cdd:cd03778   1 A*ADLEQKVLE*EASTYDGVFIWKISDFARKRQEAVAGRIPAIFSPAFYTSRYGYKMCLRIYLNGDGTGRGTHLSLFFVV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13277840 414 MKGPNDALLQWPFNQKVTLMLLDHNNREHVIDAFRPDVTSSSFQRPVSDMNIASGCPLFCPVSKMEAKNSYVRDDAIFIK 493
Cdd:cd03778  81 MKGPNDALLRWPFNQKVTLMLLDQNNREHVIDAFRPDVTSSSFQRPVNDMNIASGCPLFCPVSK*EAKNSYVRDDAIFIK 160

                ....
gi 13277840 494 AIVD 497
Cdd:cd03778 161 AIVD 164

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 13277840  31 KYLCSACKNILRRPFQAQCGHRYCSFCLTSILSSGPQNCAACV 73
Cdd:cd16639   1 KYLCSDCRNILRRPFQAQCGHRYCSYCLKKILSSGPQKCAACI 43

Tumor Necrosis Factor Receptor (TNFR) Associated Factor (TRAF) family, TRAF2 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. TRAF2 associates with the receptors TNFR-1, TNFR-2, RANK (which mediates differentiation and maturation of osteoclasts) and CD40 (which is important for the proliferation and activation of B cells), among others. It regulates distinct pathways that lead to the activation of nuclear factor-kappaB and Jun NH2-terminal kinases. TRAF2 also indirectly associates with death receptors through its interaction with TRADD (TNFR-associated death domain protein). It is involved in regulating oxidative stress or ROS-induced cell death and in the preconditioning of cells by sublethal stress for protection from subsequent injury. TRAF2 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 13277840 334 AMADLEQKVSELEVSTYDGVFIWKISDFTRKRQEAVAGRTPAIFSPAFYTSRYGYKMCLRVYLNGDGTGRGTHLSLFFVV 413
Cdd:cd03778   1 A*ADLEQKVLE*EASTYDGVFIWKISDFARKRQEAVAGRIPAIFSPAFYTSRYGYKMCLRIYLNGDGTGRGTHLSLFFVV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13277840 414 MKGPNDALLQWPFNQKVTLMLLDHNNREHVIDAFRPDVTSSSFQRPVSDMNIASGCPLFCPVSKMEAKNSYVRDDAIFIK 493
Cdd:cd03778  81 MKGPNDALLRWPFNQKVTLMLLDQNNREHVIDAFRPDVTSSSFQRPVNDMNIASGCPLFCPVSK*EAKNSYVRDDAIFIK 160

                ....
gi 13277840 494 AIVD 497
Cdd:cd03778 161 AIVD 164

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 13277840  31 KYLCSACKNILRRPFQAQCGHRYCSFCLTSILSSGPQNCAACV 73
Cdd:cd16639   1 KYLCSDCRNILRRPFQAQCGHRYCSYCLKKILSSGPQKCAACI 43

meprin and TRAF homology;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13277840    353 VFIWKISDFTRkrqeavAGRTPAIFSPAFYtsRYGYKMCLRVYLNGDgtgrgtHLSLFFVVMKGPNDALlQWPFNQKVTL 432
Cdd:smart00061   1 VLSHTFKNVSR------LEEGESYFSPSEE--HFNIPWRLKIYRKNG------FLSLYLHCEKEECDSR-KWSIEAEFTL 65

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|.
gi 13277840    433 MLLDHNNREHvidafrPDVTSSSFQRPVSdmniaSGCPLFC 473
Cdd:smart00061  66 KLVSQNGKSL------SKKDKHVFEKPSG-----WGFSKFI 95

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
                  ....*....|....*....|....*....|....*....|....*...
gi 13277840    28 LEAKYLCSACKNILRRPFQAQCGHRYCSFCLTSILSSGPqNCAACVYE 75
Cdd:TIGR00599  23 LDTSLRCHICKDFFDVPVLTSCSHTFCSLCIRRCLSNQP-KCPLCRAE 69

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 13277840     34 CSACK-NILRRPFQAQCGHRYCSFCLTSILSSGPQNCAAC 72
Cdd:smart00184   1 CPICLeEYLKDPVILPCGHTFCRSCIRKWLESGNNTCPIC 40

chromosome segregation protein SMC, primarily archaeal type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. It is found in a single copy and is homodimeric in prokaryotes, but six paralogs (excluded from this family) are found in eukarotes, where SMC proteins are heterodimeric. This family represents the SMC protein of archaea and a few bacteria (Aquifex, Synechocystis, etc); the SMC of other bacteria is described by TIGR02168. The N- and C-terminal domains of this protein are well conserved, but the central hinge region is skewed in composition and highly divergent. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13277840    236 ELQRLREHLALL---LSSFLEAQASpgtLNQVGPELLQRCQILEQKIATFENIVCVLNREVERVAVTAEACSRQHRLDQD 312
Cdd:TIGR02169  675 ELQRLRERLEGLkreLSSLQSELRR---IENRLDELSQELSDASRKIGEIEKEIEQLEQEEEKLKERLEELEEDLSSLEQ 751

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 13277840    313 KIEALSNKVQQLERSIGLKDLAMADLEQKVSELEVStYDGVFIWKISDFTRKRQEAVA 370
Cdd:TIGR02169  752 EIENVKSELKELEARIEELEEDLHKLEEALNDLEAR-LSHSRIPEIQAELSKLEEEVS 808

Tumor Necrosis Factor Receptor (TNFR) Associated Factor (TRAF) family, TRAF2 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. TRAF2 associates with the receptors TNFR-1, TNFR-2, RANK (which mediates differentiation and maturation of osteoclasts) and CD40 (which is important for the proliferation and activation of B cells), among others. It regulates distinct pathways that lead to the activation of nuclear factor-kappaB and Jun NH2-terminal kinases. TRAF2 also indirectly associates with death receptors through its interaction with TRADD (TNFR-associated death domain protein). It is involved in regulating oxidative stress or ROS-induced cell death and in the preconditioning of cells by sublethal stress for protection from subsequent injury. TRAF2 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 13277840 334 AMADLEQKVSELEVSTYDGVFIWKISDFTRKRQEAVAGRTPAIFSPAFYTSRYGYKMCLRVYLNGDGTGRGTHLSLFFVV 413
Cdd:cd03778   1 A*ADLEQKVLE*EASTYDGVFIWKISDFARKRQEAVAGRIPAIFSPAFYTSRYGYKMCLRIYLNGDGTGRGTHLSLFFVV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13277840 414 MKGPNDALLQWPFNQKVTLMLLDHNNREHVIDAFRPDVTSSSFQRPVSDMNIASGCPLFCPVSKMEAKNSYVRDDAIFIK 493
Cdd:cd03778  81 MKGPNDALLRWPFNQKVTLMLLDQNNREHVIDAFRPDVTSSSFQRPVNDMNIASGCPLFCPVSK*EAKNSYVRDDAIFIK 160

                ....
gi 13277840 494 AIVD 497
Cdd:cd03778 161 AIVD 164

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 13277840 314 IEALSNKVQQLERSIGLKDLAMADLEQKVSELEVSTYDGVFIWKISDFTRKRQEAVAGRTPAIFSPAFYTSRYGYKMCLR 393
Cdd:cd03777   1 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13277840 394 VYLNGDGTGRGTHLSLFFVVMKGPNDALLQWPFNQKVTLMLLDHN-NREHVIDAFRPDVTSSSFQRPVSDMNIASGCPLF 472
Cdd:cd03777  81 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGsSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 160

                       170       180
                ....*....|....*....|....*..
gi 13277840 473 CPVSKMEaKNSYVRDDAIFIKAIVDLT 499
Cdd:cd03777 161 VAQTVLE-NGTYIKDDTIFIKVIVDTS 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 13277840 352 GVFIWKISDFTRKRQEAVAGRTPAIFSPAFYTSRYGYKMCLRVYLNGDGTGRGTHLSLFFVVMKGPNDALLQWPFNQKVT 431
Cdd:cd03780   1 GKLIWKVTDYKMKKKEAVDGHTVSIFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVT 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 13277840 432 LMLLDHNN-REHVIDAFRPDVTSSSFQRPVSDMNIASGCPLFCPVSKME-AKNSYVRDDAIFIKAIVD 497
Cdd:cd03780  81 LMLLDQSGkKNHIMETFKADPNSSSFKRPDGEMNIASGCPRFVAHSVLEnAKNTYIKDDTLFLKVAVD 148

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 13277840 352 GVFIWKISDFTRKRQEAVAGRTPAIFSPAFYTSRYGYKMCLRVYLNGDGTGRGTHLSLFFVVMKGPNDALLQWPFNQKVT 431
Cdd:cd03776   1 GIYVWKIKNFSNLRRSMEAGSPVVIHSPGFYTSPPGYKLCARLNLSLPEARCPNYISLFVHLMQGENDSHLDWPFQGTIT 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13277840 432 LMLLDHNNREH----VIDAfRPDVtsSSFQRPVSDMNIAS-GCPLFCPVSKMEAKnSYVRDDAIFIKAIV 496
Cdd:cd03776  81 LTLLDQSEPRQniheTMMS-KPEL--LAFQRPTTDRNPKGfGYVEFAHIEDLLQR-GFVKNDTLLIKIEV 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 13277840 352 GVFIWKISDFTRKRQEAvagrtpaIFSPAFYtsRYGYKMCLRVYLNGDGTgRGTHLSLFFVVMKGPNDaLLQWPFNQKVT 431
Cdd:cd00121   1 GKHTWKIVNFSELEGES-------IYSPPFE--VGGYKWRIRIYPNGDGE-SGDYLSLYLELDKGESD-LEKWSVRAEFT 69

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 13277840 432 LMLLDHNNREHVIDAFRPDVTSSSfqrpvsdmNIASGCPLFCPVSKMEaKNSYVRDDAIFIKAIVD 497
Cdd:cd00121  70 LKLVNQNGGKSLSKSFTHVFFSEK--------GSGWGFPKFISWDDLE-DSYYLVDDSLTIEVEVK 126

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 13277840   178 HYEVCPKFPLTC-DGCGKKKIPRETFQDHVR-ACSKCRVLCRFHTVGCSEMVETENLQDH 235
Cdd:pfam02176   1 HLETCPFFPIPCpNGCCKKKILREDLPDHLElDCPKAEVPCPFKVFGCKEDVKREALQRH 60

Meprin family, MATH domain; Meprins are multidomain, highly glycosylated extracellular metalloproteases, which are either anchored to the membrane or secreted into extracellular spaces. They are expressed in renal and intestinal brush border membranes, leukocytes, and cancer cells, and are capable of cleaving growth factors, cytokines, extracellular matrix proteins, and biologically active peptides. Meprin proteases are composed of two related subunits, alpha and beta, which form homo- or hetro-complexes where the basic unit is a disulfide-linked dimer. Despite their similarity, the two subunits differ in their ability to self-associate, in proteolytic processing during biosynthesis and in substrate specificity. Both subunits are synthesized as membrane spanning proteins, however, the alpha subunit is cleaved during biosynthesis and loses its transmembrane domain. Meprin beta forms homodimers or heterotetramers while meprin alpha oligomerizes into large complexes containing 10-100 subunits. 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 13277840 354 FIWKISDFTRKRQEAVAGRtpAIFSPAFYTSR-YGYKMclRVYLNGdGTGRGTHLSLFFVVMKGPNDALLQWP-FNQKVT 431
Cdd:cd03771   4 AVWRVRNFSQLLETTPKGT--KIYSPRFYSPEgYAFQV--GLYPNG-TESYPGYTGLYFHLCSGENDDVLEWPcPNRQAT 78

                ....*..
gi 13277840 432 LMLLDHN 438
Cdd:cd03771  79 MTLLDQD 85

Meprin family, Alpha 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 alpha subunit is synthesized as a membrane spanning protein, however, it is cleaved during biosynthesis and loses its transmembrane domain. It oligomerizes into large complexes, containing 10-100 subunits (dimers that associate noncovalently), which are secreted as latent proteases and can move through extracellular spaces in a nondestructive manner. This allows delivery of the concentrated protease to sites containing activating enzymes, such as sites of inflammation, infection or cancerous growth. Meprin alpha shows preference for small or hydrophobic residues at the P1 and P1' sites of its substrate. 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 13277840 355 IWKISDFTRKRQEAVagRTPAIFSPAFYTSRyGYKMCLRVY-LNGDGTGRGTHLSLFFVVMKGPNDALLQWP-FNQKVTL 432
Cdd:cd03783   5 VWRVRNFSQILENTT--KGDVLQSPRFYSPE-GYGYGVSLYpLSNESDYSGNYTGLYFHLCSGENDAVLEWPaLNRQAII 81

                ....*.
gi 13277840 433 MLLDHN 438
Cdd:cd03783  82 TVLDQD 87

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
                ....*....|....*....|....*....|....*....|
gi 13277840  28 LEAKYLCSACKNILRRPFQAQ-CGHRYCSFCLTSILSSGP 66
Cdd:cd23126   1 LDKKYECPVCCQVLRYPVQFEeCGHRVCSSCLPELLRVEP 40

Modified RING finger, HC subclass (C3HC3D-type), found in tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and similar proteins; TRAF6, also known as interleukin-1 signal transducer or RING finger protein 85 (RNF85), is a cytoplasmic adapter protein that mediates signals induced by the tumor necrosis factor receptor (TNFR) superfamily and Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) family. It functions as a mediator involved in the activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and interferon regulatory factor pathways, as well as in IL-1R-mediated activation of NF-kappaB. TRAF6 is also an oncogene that plays a vital role in K-RAS-mediated oncogenesis. TRAF6 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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 13277840  31 KYLCSACKNILRRPFQAQCGHRYCSFCLTSILSSGPQNCAAcvyeglyeeGISILESSSAFPDNAAR 97
Cdd:cd16643   1 KYECPICLMALREPVQTPCGHRFCKACILKSIREAGHKCPV---------DNEPLLENQLFPDNFAK 58

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 13277840    34 CSACKNILRRPFQA-QCGHRYCSFCLTSILSSGPQNCAAC 72
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
                  ....*....|....*....|....*....|....*....|....*...
gi 13277840    28 LEAKYLCSACKNILRRPFQAQCGHRYCSFCLTSILSSGPqNCAACVYE 75
Cdd:TIGR00599  23 LDTSLRCHICKDFFDVPVLTSCSHTFCSLCIRRCLSNQP-KCPLCRAE 69

RING finger, HC subclass, found in Saccharomyces cerevisiae radiation sensitivity protein 18 (RAD18) and similar proteins; RAD18, also called RING-type E3 ubiquitin transferase RAD18, acts as a postreplication repair E3 ubiquitin-protein ligase that associates with the E2 ubiquitin conjugating enzyme UBC2/RAD6 to form the UBC2-RAD18 ubiquitin ligase complex involved in postreplicative repair (PRR) of damaged DNA. The UBC2-RAD18 complex cooperates with RAD5 and the UBC13-MMS2 dimer to attach mono-ubiquitin chains on 'Lys-164' of POL30, which is necessary for PRR. The UBC2-RAD18 complex is also involved in prevention of spontaneous mutations caused by 7,8-dihydro-8-oxoguanine. RAD18 is an E3 RING-finger protein belonging to the UBC2/RAD6 epistasis group. It contains a typical C3HC4-type RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 13277840  34 CSACKNILRRPFQAQCGHRYCSFCLTSILSSGPqNCAACVYE 75
Cdd:cd23148   6 CHICKDLLKAPMRTPCNHTFCSFCIRTHLNNDA-RCPLCKAE 46

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 13277840     34 CSACK-NILRRPFQAQCGHRYCSFCLTSILSSGPQNCAAC 72
Cdd:smart00184   1 CPICLeEYLKDPVILPCGHTFCRSCIRKWLESGNNTCPIC 40

Septal ring factor EnvC, activator of murein hydrolases AmiA and AmiB [Cell cycle control, cell division, chromosome partitioning];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13277840 240 LREHLALLLSSFLEAQASPGTLNQVGPELLQrcqiLEQKIATfenivcvLNREVERVAVTAEACSRQHRLDQDKIEALSN 319
Cdd:COG4942   1 MRKLLLLALLLALAAAAQADAAAEAEAELEQ----LQQEIAE-------LEKELAALKKEEKALLKQLAALERRIAALAR 69

                        90       100
                ....*....|....*....|....*..
gi 13277840 320 KVQQLERSIGLKDLAMADLEQKVSELE 346
Cdd:COG4942  70 RIRALEQELAALEAELAELEKEIAELR 96

RING finger, HC subclass, found in Dictyostelium discoideum Ras guanine nucleotide exchange factor O (RasGEFO) and similar proteins; RasGEFO, also known as RasGEF domain-containing protein O, functions as a Ras guanine-nucleotide exchange factor (RasGEFs), activating Ras by catalyzing the replacement of GDP with GTP. RasGEFs are particularly important for signaling in development and chemotaxis in many organisms, including Dictyostelium. RasGEFO contains a C3HC4-type RING-HC finger that may be responsible for E3 ubiquitin ligase activity.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 13277840  26 TRLEAKYLCSACKNILRRP-FQAQCGHRYCSFCLTSILsSGPqNCAAC 72
Cdd:cd16507   4 LNLLQSLTCGICQNLFKDPnTLIPCGHAFCLDCLTTNA-SIK-NCIQC 49

chromosome segregation protein SMC, primarily archaeal type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. It is found in a single copy and is homodimeric in prokaryotes, but six paralogs (excluded from this family) are found in eukarotes, where SMC proteins are heterodimeric. This family represents the SMC protein of archaea and a few bacteria (Aquifex, Synechocystis, etc); the SMC of other bacteria is described by TIGR02168. The N- and C-terminal domains of this protein are well conserved, but the central hinge region is skewed in composition and highly divergent. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13277840    236 ELQRLREHLALL---LSSFLEAQASpgtLNQVGPELLQRCQILEQKIATFENIVCVLNREVERVAVTAEACSRQHRLDQD 312
Cdd:TIGR02169  675 ELQRLRERLEGLkreLSSLQSELRR---IENRLDELSQELSDASRKIGEIEKEIEQLEQEEEKLKERLEELEEDLSSLEQ 751

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 13277840    313 KIEALSNKVQQLERSIGLKDLAMADLEQKVSELEVStYDGVFIWKISDFTRKRQEAVA 370
Cdd:TIGR02169  752 EIENVKSELKELEARIEELEEDLHKLEEALNDLEAR-LSHSRIPEIQAELSKLEEEVS 808

RING finger, HC subclass, found in tripartite motif-containing protein 39 (TRIM39) and similar proteins; TRIM39, also known as RING finger protein 23 (RNF23) or testis-abundant finger protein, is an E3 ubiquitin-protein ligase that plays a role in controlling DNA damage-induced apoptosis through inhibition of the anaphase promoting complex (APC/C), a multiprotein ubiquitin ligase that controls multiple cell cycle regulators, including cyclins, geminin, and others. TRIM39 also functions as a regulator of several key processes in the proliferative cycle. It directly regulates p53 stability. It modulates cell cycle progression and DNA damage responses via stabilizing p21. Moreover, TRIM39 negatively regulates the nuclear factor kappaB (NFkappaB)-mediated signaling pathway through stabilization of Cactin, an inhibitor of NFkappaB- and Toll-like receptor (TLR)-mediated transcription, which is induced by inflammatory stimulants such as tumor necrosis factor alpha. Furthermore, TRIM39 is a MOAP-1-binding protein that can promote apoptosis signaling through stabilization of MOAP-1 via the inhibition of its poly-ubiquitination process. TRIM39 belongs to the C-IV subclass of the 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.

                        10        20
                ....*....|....*....|....*..
gi 13277840  33 LCSACKNILRRPFQAQCGHRYCSFCLT 59
Cdd:cd16601   3 SCSLCKEYLKDPVIIECGHNFCRACIT 29

second RING finger, HC subclass, found in Arabidopsis thaliana ORTHRUS and similar proteins; This subfamily includes Arabidopsis thaliana ORTHRUS 1-5. They are E3 ubiquitin-protein ligases that may participate in CpG methylation-dependent transcriptional regulation and/or epigenetic transcriptional silencing. ORTHRUS 1 mediates ubiquitination with the E2 ubiquitin-conjugating enzymes UBC11, UBC8 and UBC8 homologs (e.g. UBC10, UBC11, UBC28 and UBC29) but not with UBC27, UBC30, UBC32, UBC34 and UBC36. ORTHRUS 2 and 5 mediate ubiquitination with the E2 ubiquitin-conjugating enzyme UBC11. ORTHRUS 1 and 2 promote methylation-mediated gene silencing leading, for example, to early flowering. They can bind to CpG, CpNpG, and CpNpN DNA motifs, with a strong preference for methylated forms, and with highest affinity for CpG substrates. Members of this subfamily contain two typical C3HC4-type RING-HC fingers. This model corresponds to the second one.

                        10        20        30
                ....*....|....*....|....*....|....*
gi 13277840  27 RLEAKYLCSACKNILRRPFQAQCGHRYCSFCLTSI 61
Cdd:cd23139   1 RLLKEFGCQICKKVLSLPVSTPCGHNFCKACLEAK 35