The RING-variant domain is a C4HC3 zinc-finger like motif found in a number of cellular and viral proteins; Some of these proteins have been shown both in vivo and in vitro to have ubiquitin E3 ligase activity. The RING-variant domain is reminiscent of both the RING and the PHD domains and may represent an evolutionary intermediate. To describe this domain the term PHD/LAP domain has been used in the past. Extended description: The RING-variant (RINGv) domain contains a C4HC3 zinc-finger-like motif similar to the PHD domain, while some of the spacing between the Cys/His residues follow a pattern somewhat closer to that found in the RING domain. The RINGv domain, similar to the RING, PHD and LIM domains, is thought to bind two zinc ions co-ordinated by the highly conserved Cys and His residues. RING variant domain: C-x (2) -C-x(10-45)-C-x (1) -C-x (7) -H-x(2)-C-x(11-25)-C-x(2)-C As opposed to a PHD: C-x(1-2) -C-x (7-13)-C-x(2-4)-C-x(4-5)-H-x(2)-C-x(10-21)-C-x(2)-C Classical RING domain: C-x (2) -C-x (9-39)-C-x(1-3)-H-x(2-3)-C-x(2)-C-x(4-48) -C-x(2)-C

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 8885610      53 QCRICHDEDEDTN-MDTPCSCSGTLKFAHHNCVQRWCNEKGDTVCEICR 100
Cdd:smart00744   1 ICRICHDEGDEGDpLVSPCRCKGSLKYVHQECLERWINESGNKTCEICK 49

The RING-variant domain is a C4HC3 zinc-finger like motif found in a number of cellular and viral proteins; Some of these proteins have been shown both in vivo and in vitro to have ubiquitin E3 ligase activity. The RING-variant domain is reminiscent of both the RING and the PHD domains and may represent an evolutionary intermediate. To describe this domain the term PHD/LAP domain has been used in the past. Extended description: The RING-variant (RINGv) domain contains a C4HC3 zinc-finger-like motif similar to the PHD domain, while some of the spacing between the Cys/His residues follow a pattern somewhat closer to that found in the RING domain. The RINGv domain, similar to the RING, PHD and LIM domains, is thought to bind two zinc ions co-ordinated by the highly conserved Cys and His residues. RING variant domain: C-x (2) -C-x(10-45)-C-x (1) -C-x (7) -H-x(2)-C-x(11-25)-C-x(2)-C As opposed to a PHD: C-x(1-2) -C-x (7-13)-C-x(2-4)-C-x(4-5)-H-x(2)-C-x(10-21)-C-x(2)-C Classical RING domain: C-x (2) -C-x (9-39)-C-x(1-3)-H-x(2-3)-C-x(2)-C-x(4-48) -C-x(2)-C

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 8885610      53 QCRICHDEDEDTN-MDTPCSCSGTLKFAHHNCVQRWCNEKGDTVCEICR 100
Cdd:smart00744   1 ICRICHDEGDEGDpLVSPCRCKGSLKYVHQECLERWINESGNKTCEICK 49

RING-variant domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 8885610     54 CRICHDE-DEDTNMDTPCSCSGTLKFAHHNCVQRWCNEKGDTVCEIC 99
Cdd:pfam12906   1 CRICLEEeAEDSPLIHPCRCRGSLKYVHQSCLERWLDTSANTQCEIC 47

LAP/PHD finger-like protein; Provisional

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 8885610    54 CRICHDE-DEDTNMdtpCSCSGTLKFAHHNCVQRWCNEKGDTVCEICRQQY 103
Cdd:PHA02825  11 CWICKDEyDVVTNY---CNCKNENKIVHKECLEEWINTSKNKSCKICNGPY 58

The RING-variant domain is a C4HC3 zinc-finger like motif found in a number of cellular and viral proteins; Some of these proteins have been shown both in vivo and in vitro to have ubiquitin E3 ligase activity. The RING-variant domain is reminiscent of both the RING and the PHD domains and may represent an evolutionary intermediate. To describe this domain the term PHD/LAP domain has been used in the past. Extended description: The RING-variant (RINGv) domain contains a C4HC3 zinc-finger-like motif similar to the PHD domain, while some of the spacing between the Cys/His residues follow a pattern somewhat closer to that found in the RING domain. The RINGv domain, similar to the RING, PHD and LIM domains, is thought to bind two zinc ions co-ordinated by the highly conserved Cys and His residues. RING variant domain: C-x (2) -C-x(10-45)-C-x (1) -C-x (7) -H-x(2)-C-x(11-25)-C-x(2)-C As opposed to a PHD: C-x(1-2) -C-x (7-13)-C-x(2-4)-C-x(4-5)-H-x(2)-C-x(10-21)-C-x(2)-C Classical RING domain: C-x (2) -C-x (9-39)-C-x(1-3)-H-x(2-3)-C-x(2)-C-x(4-48) -C-x(2)-C

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 8885610      53 QCRICHDEDEDTN-MDTPCSCSGTLKFAHHNCVQRWCNEKGDTVCEICR 100
Cdd:smart00744   1 ICRICHDEGDEGDpLVSPCRCKGSLKYVHQECLERWINESGNKTCEICK 49

RING-variant domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 8885610     54 CRICHDE-DEDTNMDTPCSCSGTLKFAHHNCVQRWCNEKGDTVCEIC 99
Cdd:pfam12906   1 CRICLEEeAEDSPLIHPCRCRGSLKYVHQSCLERWLDTSANTQCEIC 47

RING-CH finger, H2 subclass (C4HC3-type), found in membrane-associated RING-CH8 (MARCH8); MARCH8, also known as membrane-associated RING finger protein 8, membrane-associated RING-CH protein VIII (MARCH-VIII), RING finger protein 178 (RNF178), or cellular modulator of immune recognition (c-MIR), is a membrane-anchored E3 ubiquitin ligase that is broadly expressed. It is a functional homolog of Kaposi"s sarcoma associated-herpes virus encoded proteins, modulator of immune recognition (MIR) 1 and 2, which are involved in the evasion of host immunity. MARCH8 mediates the ubiquitination and down-regulation of immune regulatory cell surface molecules, including major histocompatibility complex class II (MHCII), CD86, transferrin receptor, HLA-DM, and Fas in immune cells. Moreover, MARCH8 controls cell surface expression of some additional proteins. It regulates the ubiquitination and lysosomal degradation of the transferrin receptor (TfR). Tumor necrosis factor-related apoptosis inducing ligand receptor 1 (TRAIL-R1) is also a physiological substrate of the endogenous MARCH8, which regulates the steady-state cell surface expression of TRAIL-R1. Meanwhile, it negatively regulates interleukin-1 (IL-1) beta-induced NF-kappaB activation by targeting the IL-1 receptor accessory protein (IL1RAP) coreceptor for ubiquitination and degradation. Furthermore, MARCH8 functions in the embryo to modulate the strength of cell adhesion by regulating the localization of E-cadherin. In addition, MARCH8 plays a role in the inhibition of inflammatory cytokine production, suggesting a new therapeutic approach to the treatment of rheumatoid arthritis (RA). MARCH8 contains an N-terminal cytoplasmic C4HC3-type RING-CH finger, also known as vRING or RINGv, a variant of C3H2C3-type RING-H2 finger and two transmembrane domains.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 8885610   54 CRICHDE-DEDTNMDTPCSCSGTLKFAHHNCVQRWCNEKGDTVCEICRQQY 103
Cdd:cd16807   8 CRICHCEgDDESPLITPCHCTGSLRFVHQACLQQWIKSSDTRCCELCKYEF 58

RING-CH finger, H2 subclass (C4HC3-type), found in membrane-associated RING-CH1 (MARCH1); MARCH1, also known as membrane-associated RING finger protein 1, membrane-associated RING-CH protein I (MARCH-I), or RING finger protein 171 (RNF171), is a membrane-anchored E3 ubiquitin ligase that is mainly expressed in cells of the immune system. It regulates antigen presentation and T-cell costimulatory functions of dendritic cells by down-regulating the cell surface expression of major histocompatibility complex class II (MHCII) and CD86 molecules. It mediates ubiquitination of MHCII and CD86 in dendritic cells (DCs). This ubiquitination induces MHCII and CD86 endocytosis, lysosomal transport, and degradation. MARCH1 also plays a regulatory role in T cell activation during immune responses, as well as in splenic DC homeostasis. Moreover, MARCH1 may regulate its own expression through dimerization and autoubiquitination. MARCH1 contains an N-terminal cytoplasmic C4HC3-type RING-CH finger, also known as vRING or RINGv, a variant of C3H2C3-type RING-H2 finger and two transmembrane domains.

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                ....*....|....*....|....*....|....*....|....*....|.
gi 8885610   54 CRICHDE-DEDTNMDTPCSCSGTLKFAHHNCVQRWCNEKGDTVCEICRQQY 103
Cdd:cd16806   7 CRICHCEgDEESPLITPCRCTGTLRFVHQACLHQWIKSSDTRCCELCKYDF 57

RING-CH finger, H2 subclass (C4HC3-type), found in membrane-associated RING-CH2 (MARCH2); MARCH2, also known as membrane-associated RING finger protein 2, membrane-associated RING-CH protein II (MARCH-II), or RING finger protein 172 (RNF172), is a Golgi-localized, membrane-associated E3 ubiquitin-protein ligase that is involved in endosomal trafficking through the binding of syntaxin 6 (STX6). It is involved in the cystic fibrosis transmembrane conductance regulator (CFTR)-associated ligand (CAL)-mediated ubiquitination and lysosomal degradation of mature CFTR through the association with adaptor proteins CAL and STX6. It also reduces the surface expression of CD86 and the transferrin receptor TFRC and regulates cell surface carvedilol-bound beta2-adrenergic receptor (beta2AR) expression. Moreover, MARCH2 interacts with and ubiquitinates PDZ domains polarity determining scaffold protein DLG1 through its PDZ-binding motif, suggesting it may function as a molecular bridge with ubiquitin ligase activity connecting endocytic tumor suppressor proteins such as syntaxins to DLG1. MARCH2 contains a C4HC3-type RING-CH finger, also known as vRING or RINGv, a variant of C3H2C3-type RING-H2 finger, in the N-terminal cytoplasmic region, two transmembrane domains in the middle region, and a PDZ-binding motif at the C-terminus.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 8885610   54 CRICHDEDEDTNMDTPCSCSGTLKFAHHNCVQRWCNEKGDTVCEICRQQY 103
Cdd:cd16808   3 CRICHEGGNGESLLSPCDCTGTLGTVHKSCLEKWLSSSNTSYCELCHTEF 52

RING-CH finger, H2 subclass (C4HC3-type), found in membrane-associated RING finger protein MARCH4, MARCH9, and similar proteins; This subfamily includes the closely related MARCH4 and MARCH9, both belonging to the family of MARCH E3 ligases. They downregulate major histocompatibility complex-I (MHC-I). In the presence of MARCH4 or MARCH9, MHC-I can be ubiquitinated and rapidly internalized by endocytosis, whereas MHC-I molecules lacking lysines in their cytoplasmic tail are resistant to downregulation. Moreover, MARCH4 and MARCH9, but not other MARCH proteins, can associate with Mult1 and prevent Mult1 expression at the cell surface in a lysine-dependent manner that can be reversed by heat shocking the cells. Both MARCH4 and MARCH9 contain an N-terminal C4HC3-type RING-CH finger, also known as vRING or RINGv, a variant of C3H2C3-type RING-H2 finger, followed by two transmembrane regions.

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                ....*....|....*....|....*....|....*....|....*....|.
gi 8885610   53 QCRICHDEDEDTNMDTPCSCSGTLKFAHHNCVQRWCNEKGDTVCEICRQQY 103
Cdd:cd16811   1 LCRICFQGPEQGELLSPCRCDGSVRCTHQPCLIKWISERGSWSCELCYYKY 51

RING-CH finger, H2 subclass (C4HC3-type), found in membrane-associated RING finger proteins MARCH4, MARCH9, MARCH11, and similar proteins; MARCH4 and MARCH9 are closely related to each other. They downregulate major histocompatibility complex-I (MHC-I). Moreover, MARCH4 and MARCH9, but not other MARCH proteins, can associate with Mult1 and prevent Mult1 expression at the cell surface in a lysine-dependent manner that can be reversed by heat shocking the cells. MARCH11 is a transmembrane RING-finger ubiquitin ligase that is predominantly expressed in developing spermatids in a stage-specific manner and is localized to trans-Golgi network (TGN) vesicles and multivesicular bodies (MVBs). It mediates selective protein sorting via the TGN-MVB transport pathway through its ubiquitin ligase activity. SAMT family proteins have been identified as substrates of MARCH11 in mouse spermatids, suggesting that MARCH11 plays a role in mammalian spermiogenesis. Moreover, MARCH11 targets CD4 for ubiquitination. It also forms complexes with the adaptor protein complex-1 and with fucose-containing glycoproteins including ubiquitinated forms. All subfamily members contain an N-terminal C4HC3-type RING-CH finger, also known as vRING or RINGv, a variant of C3H2C3-type RING-H2 finger, followed by two transmembrane regions.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 8885610   54 CRICHDEDEDTNMDTPCSCSGTLKFAHHNCVQRWCNEKGDTVCEICRQQY 103
Cdd:cd16700   2 CRICFQGAEQGELLSPCRCDGSVRCTHQPCLLKWISERGSWSCELCYYRY 51

RING-CH finger, H2 subclass (C4HC3-type), found in membrane-associated RING-CH3 (MARCH3); MARCH3, also known as membrane-associated RING finger protein 3, or membrane-associated RING-CH protein III (MARCH-III), or RING finger protein 173 (RNF173), is an E3 ubiquitin-protein ligase that is broadly expressed and is found at relatively high levels in spleen, colon, and lung. It is localized to early endosomes, binds to MARCH2 and syntaxin 6, and is involved in the regulation of vesicular trafficking and fusion of the transport vesicles in endosomes. MARCH3 is the closest homolog of MARCH2 and it is also a functional homolog of K3 and K5 viral ubiquitin E3 ligases related to immune-evasion strategies used by Kaposi's sarcoma-associated herpesvirus (KSHV). Its E2 specificity significantly overlaps that of MARCH2. MARCH3 contains a C4HC3-type RING-CH finger, also known as vRING or RINGv, a variant of C3H2C3-type RING-H2 finger, in the N-terminal cytoplasmic region, two transmembrane domains in the middle region, and a PDZ-binding motif at the C-terminus. The RING-CH finger and PDZ-binding motif are essential for the subcellular localization of MARCH3 and the inhibitory effect on transferrin uptake.

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                ....*....|....*....|....*....|....*....|....*....|
gi 8885610   54 CRICHDEDEDTNMDTPCSCSGTLKFAHHNCVQRWCNEKGDTVCEICRQQY 103
Cdd:cd16809   7 CRICHEGSSQEDLLSPCECTGTLGTIHRSCLEHWLSSSNTSYCELCHFRF 56

RING-CH finger, H2 subclass (C4HC3-type), found in membrane-associated RING-CH11 (MARCH11); MARCH11, also known as membrane-associated RING finger protein 11, or membrane-associated RING-CH protein XI (MARCH-XI), is a transmembrane RING-finger ubiquitin ligase that is predominantly expressed in developing spermatids in a stage-specific manner and is localized to trans-Golgi network (TGN) vesicles and multivesicular bodies (MVBs). It mediates selective protein sorting via the TGN-MVB transport pathway through its ubiquitin ligase activity. SAMT family proteins have been identified as substrates of MARCH11 in mouse spermatids, suggesting that MARCH11 plays a role in mammalian spermiogenesis. Moreover, MARCH11 targets CD4 for ubiquitination. It also forms complexes with the adaptor protein complex-1 and with fucose-containing glycoproteins including ubiquitinated forms. MARCH11 contains an N-terminal C4HC3-type RING-CH finger, also known as vRING or RINGv, a variant of C3H2C3-type RING-H2 finger, and two transmembrane domains. In addition, it harbors a proline-rich region, a tyrosine-based motif, and a PDZ binding motif.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 8885610   54 CRICHDEDEDTNMDTPCSCSGTLKFAHHNCVQRWCNEKGDTVCEICRQQYK 104
Cdd:cd16810   3 CKICFQGPEQGELLNPCRCDGSVRYTHQLCLLKWISERGSWTCELCCYRYH 53

RING-CH finger, H2 subclass (C4HC3-type), found in membrane-associated MARCH7, MARCH10, and similar proteins; This subfamily includes two closely related membrane-associated RING-CH proteins, MARCH7 and MARCH10, both of which are predicted to have no transmembrane spanning region, but do harbor a C4HC3-type RING-CH finger, also known as vRING or RINGv, a variant of C3H2C3-type RING-H2 finger, that is responsible for E3 activity. MARCH7, also known as MARCH-VII, RNF177, or axotrophin, is a ubiquitin E3 ligase expressed in multiple types of cells and tissues, including stem cells and precursor cells, and is predominantly localized on the plasma membrane, and cytoplasm. MARCH7 is involved in T cell proliferation and neuronal development. It also participates in the regulation of cytoskeleton re-organization, cellular migration and invasion, cell proliferation, and tumorigenesis in ovarian carcinoma cells. Moreover, MARCH7 modulates nuclear factor kappaB (NF-kappaB) and Wnt/beta-catenin pathways. It has been identified as an authentic target of miR-101. It ubiquitinates tau protein in vitro, impairing microtubule binding. MARCH10, also known as MARCH-X or RNF190, is a microtubule-associated E3 ubiquitin ligase of developing spermatids and is involved in spermiogenesis by regulating the formation and maintenance of the flagella. It is localized to the principal piece of elongating spermatids. in developing spermatids.

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                ....*....|....*....|....*....|....*....|....*....|....*..
gi 8885610   54 CRICHDEDEDTN--MDTPCSCSGTLKFAHHNCVQRWCNEK--------GDTVCEICR 100
Cdd:cd16703   5 CRICQTAGDSTSnqLIEPCQCTGSLQLVHQECLKKWLISKiqsgaeldAVKTCEMCK 61

LAP/PHD finger-like protein; Provisional

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 8885610    54 CRICHDE-DEDTNMdtpCSCSGTLKFAHHNCVQRWCNEKGDTVCEICRQQY 103
Cdd:PHA02825  11 CWICKDEyDVVTNY---CNCKNENKIVHKECLEEWINTSKNKSCKICNGPY 58