FERM domain C-lobe of E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP; also called inducible degrader of the LDL receptor, IDOL); MYLIP/IDOL is a regulator of the LDL receptor (LDLR) pathway via the nuclear receptor liver X receptor (LXR). In response to cellular cholesterol loading, the activation of LXR leads to the induction of MYLIP expression. MYLIP stimulates ubiquitination of the LDLR on its cytoplasmic tail, directing its degradation. The LXR-MYLIP-LDLR pathway provides a complementary pathway to sterol regulatory element-binding proteins for the feedback inhibition of cholesterol uptake. MYLIP has an N-terminal FERM domain and in some cases a C-terminal RING domain. The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031 185 YGIEWHAVRDSEGQKLLIGVGPEGISICKEDFSPINRIAYPVVQMATQSGKNVYLTVTKESGNSIVLLFKMISTRAASGL 264
Cdd:cd13195   1 YGVEFFEVRNIEGQKLLIGVGPHGITICNDDFEVIERIPYTAIQMATSSGRVFTLTYLSDDGSVKVLEFKLPSTRAASGL 80

                        90       100       110
                ....*....|....*....|....*....|.
gi 30841031 265 YRAITETHAFYRCDTVTSAVMMQYSRDLKGH 295
Cdd:cd13195  81 YRAITEKHAFYRCETVRSAVTDQFSRDLKGT 111

Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031      5 VTRPDAVLMEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFT-GSKGESLWLNLRNRISQQMDGLAPYRLKLRVKFFVE 83
Cdd:smart00295   4 VYLLDGTTLEFEVDSSTTAEELLETVCRKLGIRESEYFGLQFEdPDEDLRHWLDPAKTLLDQDVKSEPLTLYFRVKFYPP 83

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031     84 PHLILQE-QTRHI-FFLHIKESLLAGHLQCSPEQAVELSALLAQTKFGDYNQNT-------AQYSY--EDLCEKELSSST 152
Cdd:smart00295  84 DPNQLKEdPTRLNlLYLQVRNDILEGRLPCPEEEALLLAALALQAEFGDYDEELhdlrgelSLKRFlpKQLLDSRKLKEW 163

                          170       180       190
                   ....*....|....*....|....*....|....*...
gi 30841031    153 LNSIVAKHKELEGISQASAEYQVLQIVSAMENYGIEWH 190
Cdd:smart00295 164 RERIVELHKELIGLSPEEAKLKYLELARKLPTYGVELF 201

FERM domain C-lobe of E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP; also called inducible degrader of the LDL receptor, IDOL); MYLIP/IDOL is a regulator of the LDL receptor (LDLR) pathway via the nuclear receptor liver X receptor (LXR). In response to cellular cholesterol loading, the activation of LXR leads to the induction of MYLIP expression. MYLIP stimulates ubiquitination of the LDLR on its cytoplasmic tail, directing its degradation. The LXR-MYLIP-LDLR pathway provides a complementary pathway to sterol regulatory element-binding proteins for the feedback inhibition of cholesterol uptake. MYLIP has an N-terminal FERM domain and in some cases a C-terminal RING domain. The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031 185 YGIEWHAVRDSEGQKLLIGVGPEGISICKEDFSPINRIAYPVVQMATQSGKNVYLTVTKESGNSIVLLFKMISTRAASGL 264
Cdd:cd13195   1 YGVEFFEVRNIEGQKLLIGVGPHGITICNDDFEVIERIPYTAIQMATSSGRVFTLTYLSDDGSVKVLEFKLPSTRAASGL 80

                        90       100       110
                ....*....|....*....|....*....|.
gi 30841031 265 YRAITETHAFYRCDTVTSAVMMQYSRDLKGH 295
Cdd:cd13195  81 YRAITEKHAFYRCETVRSAVTDQFSRDLKGT 111

Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031      5 VTRPDAVLMEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFT-GSKGESLWLNLRNRISQQMDGLAPYRLKLRVKFFVE 83
Cdd:smart00295   4 VYLLDGTTLEFEVDSSTTAEELLETVCRKLGIRESEYFGLQFEdPDEDLRHWLDPAKTLLDQDVKSEPLTLYFRVKFYPP 83

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031     84 PHLILQE-QTRHI-FFLHIKESLLAGHLQCSPEQAVELSALLAQTKFGDYNQNT-------AQYSY--EDLCEKELSSST 152
Cdd:smart00295  84 DPNQLKEdPTRLNlLYLQVRNDILEGRLPCPEEEALLLAALALQAEFGDYDEELhdlrgelSLKRFlpKQLLDSRKLKEW 163

                          170       180       190
                   ....*....|....*....|....*....|....*...
gi 30841031    153 LNSIVAKHKELEGISQASAEYQVLQIVSAMENYGIEWH 190
Cdd:smart00295 164 RERIVELHKELIGLSPEEAKLKYLELARKLPTYGVELF 201

FERM central domain; This domain is the central structural domain of the FERM domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031    84 PHLILQEQTRHIFFLHIKESLLAGHLQCSPEQAVELSALLAQTKFGDYNQNTAQYSYEDL--------CEKELSSSTLNS 155
Cdd:pfam00373   3 ELLLQDEVTRHLLYLQAKDDILEGRLPCSEEEALLLAALQLQAEFGDYQPSSHTSEYLSLesflpkqlLRKMKSKELEKR 82

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 30841031   156 IVAKHKELEGISQASAEYQVLQIVSAMENYGIEWH 190
Cdd:pfam00373  83 VLEAHKNLRGLSAEEAKLKYLQIAQSLPTYGVEFF 117

FERM domain B-lobe; The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases, the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031  92 TRHIFFLHIKESLLAGHLQCSPEQAVELSALLAQTKFGDYNQNTAQYSYEDL--------CEKELSSSTLNSIVAKHKEL 163
Cdd:cd14473   1 TRYLLYLQVKRDILEGRLPCSEETAALLAALALQAEYGDYDPSEHKPKYLSLkrflpkqlLKQRKPEEWEKRIVELHKKL 80

                        90
                ....*....|....*..
gi 30841031 164 EGISQASAEYQVLQIVS 180
Cdd:cd14473  81 RGLSPAEAKLKYLKIAR 97

FERM C-terminal PH-like domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031   194 DSEGQKLLIGVGPEGISICKEDFSPINRIAYPVVQMATQSGKNVYLTVTKESGnSIVLLFKMISTRAASGLYRAITETHA 273
Cdd:pfam09380   1 DKEGTDLWLGVSAKGILVYEDNNKILNLFPWREIRKISFKRKKFLIKLRDKSS-EETLGFYTESSRACKYLWKLCVEQHT 79

                  ....
gi 30841031   274 FYRC 277
Cdd:pfam09380  80 FFRL 83

FERM domain C-lobe of E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP; also called inducible degrader of the LDL receptor, IDOL); MYLIP/IDOL is a regulator of the LDL receptor (LDLR) pathway via the nuclear receptor liver X receptor (LXR). In response to cellular cholesterol loading, the activation of LXR leads to the induction of MYLIP expression. MYLIP stimulates ubiquitination of the LDLR on its cytoplasmic tail, directing its degradation. The LXR-MYLIP-LDLR pathway provides a complementary pathway to sterol regulatory element-binding proteins for the feedback inhibition of cholesterol uptake. MYLIP has an N-terminal FERM domain and in some cases a C-terminal RING domain. The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031 185 YGIEWHAVRDSEGQKLLIGVGPEGISICKEDFSPINRIAYPVVQMATQSGKNVYLTVTKESGNSIVLLFKMISTRAASGL 264
Cdd:cd13195   1 YGVEFFEVRNIEGQKLLIGVGPHGITICNDDFEVIERIPYTAIQMATSSGRVFTLTYLSDDGSVKVLEFKLPSTRAASGL 80

                        90       100       110
                ....*....|....*....|....*....|.
gi 30841031 265 YRAITETHAFYRCDTVTSAVMMQYSRDLKGH 295
Cdd:cd13195  81 YRAITEKHAFYRCETVRSAVTDQFSRDLKGT 111

Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031      5 VTRPDAVLMEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFT-GSKGESLWLNLRNRISQQMDGLAPYRLKLRVKFFVE 83
Cdd:smart00295   4 VYLLDGTTLEFEVDSSTTAEELLETVCRKLGIRESEYFGLQFEdPDEDLRHWLDPAKTLLDQDVKSEPLTLYFRVKFYPP 83

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031     84 PHLILQE-QTRHI-FFLHIKESLLAGHLQCSPEQAVELSALLAQTKFGDYNQNT-------AQYSY--EDLCEKELSSST 152
Cdd:smart00295  84 DPNQLKEdPTRLNlLYLQVRNDILEGRLPCPEEEALLLAALALQAEFGDYDEELhdlrgelSLKRFlpKQLLDSRKLKEW 163

                          170       180       190
                   ....*....|....*....|....*....|....*...
gi 30841031    153 LNSIVAKHKELEGISQASAEYQVLQIVSAMENYGIEWH 190
Cdd:smart00295 164 RERIVELHKELIGLSPEEAKLKYLELARKLPTYGVELF 201

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain and F1 sub-domain, found in FERM (Four.1/Ezrin/Radixin/Moesin) family proteins; FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain is present at the N-terminus of a large and diverse group of proteins that mediate linkage of the cytoskeleton to the plasma membrane. FERM-containing proteins are ubiquitous components of the cytocortex and are involved in cell transport, cell structure and signaling functions. The FERM domain is made up of three sub-domains, F1, F2, and F3. The family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N), which is structurally similar to ubiquitin.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031   1 MLCYVTRPDAVLMEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGESLWLNLRNRISQQMDGLAPYRLKLRVKF 80
Cdd:cd01765   1 ISCRVRLLDGTELTLEVSKKATGQELFDKVCEKLNLLEKDYFGLFYEDNDGQKHWLDLDKKISKQLKRSGPYQFYFRVKF 80

FERM N-terminal domain; This domain is the N-terminal ubiquitin-like structural domain of the FERM domain.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 30841031     5 VTRPDAVLMEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGESLWLNLRNRISQQMD 67
Cdd:pfam09379   1 VRLLDGTVLEFDVQPKATGQVLLDQVCNHLNLKEKDYFGLQFLDDNGEHRWLDLSKRLSKQAP 63

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM, RhoGEF and pleckstrin domain-containing protein 1 (FARP1) and similar proteins; This family includes the F1 sub-domain of FERM, RhoGEF and pleckstrin domain-containing proteins FARP1, FARP2, and FERM domain-containing protein 7 (FRMD7). FARP1, also termed chondrocyte-derived ezrin-like protein (CDEP), or pleckstrin homology (PH) domain-containing family C member 2 (PLEKHC2), is a neuronal activator of the RhoA GTPase. It promotes outgrowth of developing motor neuron dendrites. It also regulates excitatory synapse formation and morphology, as well as activates the GTPase Rac1 to promote F-actin assembly. FARP2, also termed FERM domain including RhoGEF (FIR), or Pleckstrin homology (PH) domain-containing family C member 3, is a Dbl-family guanine nucleotide exchange factor (GEF) that activates Rac1 or Cdc42 in response to upstream signals, suggesting roles in regulating processes such as neuronal axon guidance and bone homeostasis. It is also a key molecule involved in the response of neuronal growth cones to class-3 semaphorins. FRMD7 plays an important role in neuronal development and is involved in the regulation of F-actin, neurofilament, and microtubule dynamics. All family members contain a FERM domain that is made up of three sub-domains, F1, F2, and F3. This family corresponds to F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 30841031   9 DAVLMEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGESLWLNLRNRISQQMDGLAPYRLKLRVKFF 81
Cdd:cd17098   9 DDTVHIFQVQQKALGEVLFDQVCKHLNLLESDYFGLEFTDPEGNKCWLDPEKPILRQVKRPKDVVFKFVVKFY 81

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in erythrocyte membrane protein band 4.1-like 5 (EPB41L5) and similar proteins; This family includes FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in erythrocyte membrane protein band 4.1-like proteins, EPB41L5 and EPB41L4B. EPB41L5 is a mesenchymal-specific protein that is an integral component of the ARF6-based pathway. EPB41L4B is a positive regulator of keratinocyte adhesion and motility, suggesting a role in wound healing. It also promotes cancer metastasis in melanoma, prostate cancer and breast cancer. Both EPB41L5 and EPB41L4B contain a FERM domain that is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 30841031   3 CYVTRPDAVLMEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGESLWLNLRNRISQQMDGLAPYRLKLRVKFF 81
Cdd:cd17108   3 CKVILLDGTDLSIELPKKAKGQELYEQVFYHLDLIEKDYFGLQFMDAAQVQHWLDPTKKIKKQVKIGPPYTLRFRVKFY 81

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in the ERM family proteins, Ezrin, Radixin, and Moesin; The ezrin-radixin-moesin (ERM) family includes a group of closely related cytoskeletal proteins that plays an essential role in microvilli formation, T-cell activation, and tumor metastasis through providing a regulated linkage between F-actin and membrane-associated proteins. These proteins may also function in signaling cascades that regulate the assembly of actin stress fibers. The ERM proteins consist of an N-terminal FERM domain, a coiled-coil (CC) domain and a C-terminal tail segment (C-tail) containing a well-defined actin-binding motif. They exist in two states, a dormant state in which the FERM domain binds to its own C-terminal tail and thereby precludes binding of some partner proteins, and an activated state, in which the FERM domain binds to one of many membrane binding proteins and the C-terminal tail binds to F-actin. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031   5 VTRPDAVLmEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGESLWLNLRNRISQQ-MDGLAPYRLKLRVKFFVE 83
Cdd:cd17187   5 VTTMDAEL-EFAIQPNTTGKQLFDQVVKTIGLREIWFFGLQYVDSKGYSTWLKLNKKVLSQdVKKENPLQFKFRAKFYPE 83

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in erythrocyte membrane protein band 4.1-like 5 (EPB41L5); EPB41L5 is a mesenchymal-specific protein that is an integral component of the ARF6-based pathway. It is normally induced during epithelial-mesenchymal transition (EMT) by an EMT-related transcriptional factor, ZEB1, which drives ARF6-based invasion, metastasis and drug resistance. EPB41L5 also binds to paxillin to enhance integrin/paxillin association, and thus promotes focal adhesion dynamics. Moreover, EPB41L5 acts as a substrate for the E3 ubiquitin ligase Mind bomb 1 (Mib1), which is essential for activation of Notch signaling. EPB41L5 is a member of the band 4.1/Nbl4 (novel band 4.1-like protein 4) group of the FERM protein superfamily. It contains a FERM domain that is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 30841031   3 CYVTRPDAVLMEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGESLWLNLRNRISQQMDGLAPYRLKLRVKFF 81
Cdd:cd17205   5 CRVSLLDGTDVSVDLPKKAKGQELFEQIMYHLDLIEKDYFGLRFMDSAQVAHWLDVTKSIKKQVKIGPPYCLHLRVKFY 83

FERM domain C-lobe of Protein 4.1 family; The protein 4.1 family includes four well-defined members: erythroid protein 4.1 (4.1R), the best known and characterized member, 4.1G (general), 4.1N (neuronal), and 4.1 B (brain). The less well understood 4.1O/FRMD3 is not a true member of this family and is not included in this hierarchy. Besides three highly conserved domains, FERM, SAB (spectrin and actin binding domain) and CTD (C-terminal domain), the proteins from this family contain several unique domains: U1, U2 and U3. FERM domains like other members of the FERM domain superfamily have a cloverleaf architecture with three distinct lobes: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The brain is a particularly rich source of protein 4.1 isoforms. The various 4.1R, 4.1G, 4.1N, and 4.1B mRNAs are all expressed in distinct patterns within the brain. It is likely that 4.1 proteins play important functional roles in the brain including motor coordination and spatial learning, postmitotic differentiation, and synaptic architecture and function. In addition they are found in nonerythroid, nonneuronal cells where they may play a general structural role in nuclear architecture and/or may interact with splicing factors. The FERM C domain is the third structural domain within the FERM domain. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031 185 YGIEWHAVRDSEGQKLLIGVGPEGISICKEDFSpINRIAYPVVQMATQSGKNVYLTVTK-ESGNS-IVLLFKMISTRAAS 262
Cdd:cd13184   1 YGVDLHPAKDSEGVDIMLGVCSSGLLVYRDRLR-INRFAWPKVLKISYKRNNFYIKIRPgEFEQYeTTIGFKLPNHRAAK 79

                        90
                ....*....|....
gi 30841031 263 GLYRAITETHAFYR 276
Cdd:cd13184  80 RLWKVCVEHHTFFR 93

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in erythrocyte membrane protein band 4.1-like protein 1 (EPB41L1) and similar proteins; EPB41L1, also termed neuronal protein 4.1 (4.1N), belongs to the skeletal protein 4.1 family that is involved in cellular processes such as cell adhesion, migration and signaling. It is a cytoskeleton-associated protein that may serve as a tumor suppressor in solid tumors. It suppresses hypoxia-induced epithelial-mesenchymal transition in epithelial ovarian cancer (EOC) cells. The down-regulation of EPB41L1 expression is a critical step for non-small cell lung cancer (NSCLC) development. Moreover, EPB41L1 functions as a linker protein between inositol 1,4,5-trisphosphate receptor type1 (IP3R1) and actin filaments in neurons. EPB41L1 contains a FERM domain, a spectrin and actin binding (SAB) domain, and a C-terminal domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031   1 MLCYVTRPDAVLMEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGESLWLNLRNRISQQMDGlAPYRLKLRVKF 80
Cdd:cd17201   2 AICKVTLLDGSEYECEVEKHARGQVLFDTVCEHLNLLEKDYFGLTFCDTESQKNWLDPSKEIKKQIRS-GPWHFAFTVKF 80

                .
gi 30841031  81 F 81
Cdd:cd17201  81 Y 81

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 30841031   383 EAMLCMACCEEEINSTFCPCGHTVCCESCAAQL----QSCPVCRSRVEHV 428
Cdd:pfam13920   1 EDLLCVICLDRPRNVVLLPCGHLCLCEECAERLlrkkKKCPICRQPIESV 50

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in radixin and similar proteins; Radixin is a member of the ezrin/radixin/moesin (ERM) family of cytoskeletal proteins that plays an essential role in microvilli formation, T-cell activation, and tumor metastasis through providing a regulated linkage between F-actin and membrane-associated proteins. These proteins may also function in signaling cascades that regulate the assembly of actin stress fibers. The ERM proteins consist of an N-terminal FERM domain, a coiled-coil (CC) domain and a C-terminal tail segment (C-tail) containing a well-defined actin-binding motif. The C-terminal domain can fold back to bind to the FERM domain forming an autoinhibited conformation. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). Radixin plays important roles in cell polarity, cell motility, invasion and tumor progression. It mediates the binding of F-actin to the plasma membrane after a conformational activation through Akt2-dependent phosphorylation at Thr564. It is also involved in reversal learning and short-term memory by regulating synaptic GABAA receptor density.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031   5 VTRPDAVLmEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGESLWLNLRNRISQQ-MDGLAPYRLKLRVKFFVE 83
Cdd:cd17238   5 VTTMDAEL-EFAIQPNTTGKQLFDQVVKTVGLREVWFFGLQYVDSKGYSTWLKLNKKVTQQdVKKENPLQFKFRAKFFPE 83

RING finger, HC subclass, found in inhibitor of apoptosis proteins (IAPs); IAPs are frequently overexpressed in cancer and associated with tumor cell survival, chemoresistance, disease progression, and poor prognosis. They function primarily as negative regulators of cell death. They regulate caspases and apoptosis through the inhibition of specific members of the caspase family of cysteine proteases. In addition, IAPs has been implicated in a multitude of other cellular processes, including inflammatory signalling and immunity, mitogenic kinase signalling, proliferation and mitosis, as well as cell invasion and metastasis. IAPs in this family includes cellular inhibitor of apoptosis protein c-IAP1 (BIRC2) and c-IAP2 (BIRC3), XIAP (BIRC4), BIRC7, and BIRC8, all of which contain three N-terminal baculoviral IAP repeat (BIR) domains that enable interactions with proteins, a ubiquitin-association (UBA) domain that is responsible for the binding of polyubiquitin (polyUb), and a C3HC4-type RING-HC finger at the carboxyl terminus that is required for ubiquitin ligase activity. The UBA domain is only absent in mammalian homologs of BIRC7. Moreover, c-IAPs contains an additional caspase activation and recruitment domain (CARD) between the UBA and C3HC4-type RING-HC domains. The CARD domain may serve as a protein interaction surface.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 30841031 384 AMLCMACCEEEINSTFCPCGHTVCCESCAAQLQSCPVCRS 423
Cdd:cd16510   1 EKLCKICMDREVNIVFLPCGHLVTCAQCAASLRKCPICRT 40

RING finger, HC subclass, found in apoptosis protein c-IAP1, c-IAP2, livin, and similar proteins; The cellular inhibitor of apoptosis protein c-IAPs function as ubiquitin E3 ligases that mediate the ubiquitination of substrates involved in apoptosis, nuclear factor-kappaB (NF-kappaB) signaling, and oncogenesis. Unlike other IAPs, such as XIAP, c-IAPs exhibit minimal binding to caspases and may not play an important role in the inhibition of these proteases. c-IAP1, also known as baculoviral IAP repeat-containing protein BIRC2, IAP-2, RING finger protein 48, or TNFR2-TRAF-signaling complex protein 2, is a potent regulator of the tumor necrosis factor (TNF) receptor family and NF-kappaB signaling pathways in the cytoplasm. It can also regulate E2F1 transcription factor-mediated control of cyclin transcription in the nucleus. c-IAP2, also known as BIRC3, IAP-1, apoptosis inhibitor 2 (API2), or IAP homolog C, also influences ubiquitin-dependent pathways that modulate innate immune signalling by activation of NF-kappaB. c-IAPs contain three N-terminal baculoviral IAP repeat (BIR) domains that enable interactions with proteins, a ubiquitin-association (UBA) domain that is responsible for the binding of polyubiquitin (polyUb), a caspase activation and recruitment domain (CARD) that serves as a protein interaction surface, and a C3HC4-type RING-HC finger at the carboxyl terminus that is required for ubiquitin ligase activity. Livin, also known as baculoviral IAP repeat-containing protein 7 (BIRC7), kidney inhibitor of apoptosis protein (KIAP), melanoma inhibitor of apoptosis protein (ML-IAP), or RING finger protein 50, was identified as the melanoma IAP. It plays crucial roles in apoptosis, cell proliferation, and cell cycle control. Its anti-apoptotic activity is regulated by the inhibition of caspase-3, -7, and -9. Its E3 ubiquitin-ligase-like activity promotes degradation of Smac/DIABLO, a critical endogenous regulator of all IAPs. Unlike other family members, mammalian livin contains a single BIR domain and a C3HC4-type RING-HC finger. The UBA domain can be detected in non-mammalian homologs of livin.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 30841031 378 LRKLKEAMLCMACCEEEINSTFCPCGHTVCCESCAAQLQSCPVCRSRV 425
Cdd:cd16713   1 LRRLQEERTCKVCMDKEVSIVFIPCGHLVVCTECAPSLRKCPICRATI 48

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM domain-containing protein 3 (FRMD3) and similar proteins; FRMD3, also termed band 4.1-like protein 4O, or ovary type protein 4.1 (4.1O), belongs to the 4.1 protein superfamily, which share the highly conserved membrane-association FERM domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). FRMD3 is involved in maintaining cell shape and integrity. It also functions as a tumour suppressor in non-small cell lung carcinoma (NSCLC). Some single nucleotide polymorphisms (SNPs) located in FRMD3 have been associated with diabetic kidney disease (DKD) in different ethnicities.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 30841031   8 PDAVLMEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGESLWLNLRNRISQQMDGLAPYRLKLRVKFF 81
Cdd:cd17102   9 DDSEVICCEFKKDTKGQFLLDYVCNYLNLLEKDYFGLRYVDTEKQRHWLDPNKSIYKQLKGVPPYVLCFRVKFY 82

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in erythrocyte membrane protein band 4.1-like proteins; The family includes erythrocyte membrane protein band 4.1-like proteins EPB41L1/4.1N, EPB41L2/4.1G, and EPB41L3/4.1B. They belong to the skeletal protein 4.1 family that is involved in cellular processes such as cell adhesion, migration and signaling. EPB41L1 is a cytoskeleton-associated protein that may serve as a tumor suppressor in solid tumors. EPB41L2 is involved in cellular processes such as cell adhesion, migration and signaling. EPB41L3 also acts as a tumor suppressor implicated in a variety of meningiomas and carcinomas. Members in this family contain a FERM domain, a spectrin and actin binding (SAB) domain, and a C-terminal domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031   1 MLCYVTRPDAVLMEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGESLWLNLRNRISQQMDGlAPYRLKLRVKF 80
Cdd:cd17106   2 QQCKVLLLDGTEYTCEVEKRAKGQVLFDKVCEHLNLLEKDYFGLTYRDAQDQKNWLDPAKEIKKQIRS-GPWLFSFNVKF 80

                .
gi 30841031  81 F 81
Cdd:cd17106  81 Y 81

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM domain-containing protein 7 (FRMD7); FRMD7 plays an important role in neuronal development and is involved in the regulation of F-actin, neurofilament, and microtubule dynamics. It interacts with the Rho GTPase regulator, RhoGDIalpha, and activates the Rho subfamily member Rac1, which regulates reorganization of actin filaments and controls neuronal outgrowth. Mutations in the FRMD7 gene are responsible for the X-linked idiopathic congenital nystagmus (ICN), a disease which affects ocular motor control. FRMD7 contains a FERM domain, and a pleckstrin homology (PH) domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 30841031  17 VEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGESLWLNLRNRISQQMDGLAPYRLKLRVKFF 81
Cdd:cd17188  18 VDQKSTGKDLFNMSCSHLNLVEKEYFGLEFRNHAGNNVWLELLKPITKQIKNPKELIFKFTVKFF 82

RING finger, HC subclass, found in Dictyostelium discoideum Cbl-like protein A (CblA) and similar proteins; CblA is a Dictyostelium homolog of the Cbl proteins which are multi-domain proteins acting as key negative regulators of various receptor and non-receptor tyrosine kinase signaling. CblA upregulates STATc tyrosine phosphorylation by downregulating PTP3, the protein tyrosine phosphatase responsible for dephosphorylating STATc. STATc is a signal transducer and activator of transcription protein. Like other Cbl proteins, CblA contains a tyrosine-kinase-binding domain (TKB), a proline-rich domain, a C3HC4-type RING-HC finger, and an ubiquitin-associated (UBA) domain. TKB, also known as a phosphotyrosine binding PTB domain, is composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain. This family also includes Drosophila melanogaster defense repressor 1 (Dnr1) that was identified as an inhibitor of Dredd activity in the absence of a microbial insult in Drosophila S2 cells. It inhibits the Drosophila initiator caspases Dredd and Dronc. Moreover, Dnr1 acts as a negative regulator of the Imd (immune deficiency) innate immune-response pathway. Its mutations cause neurodegeneration in Drosophila by activating the innate immune response in the brain. Dnr1 contains a FERM N-terminal domain followed by a region rich in glutamine and serine residues, a central FERM domain, and a C-terminal C3HC4-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 30841031 383 EAMLCMACCEEEINSTFCPCGHTVCCESCAAQLQSCPVCRSRVEHVQHVY 432
Cdd:cd16501   4 DADLCVVCMDAPIDTVFLECGHLACCRLCSKRLRVCPICRQPISRVVRIF 53

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in moesin and similar proteins; Moesin, also termed membrane-organizing extension spike protein, is a member of the ezrin/radixin/moesin (ERM) family of cytoskeletal proteins that plays an essential role in microvilli formation, T-cell activation, and tumor metastasis through providing a regulated linkage between F-actin and membrane-associated proteins. These proteins may also function in signaling cascades that regulate the assembly of actin stress fibers. The ERM proteins consist of an N-terminal FERM domain, a coiled-coil (CC) domain and a C-terminal tail segment (C-tail) containing a well-defined actin-binding motif. The C-terminal domain can fold back to bind to the FERM domain forming an autoinhibited conformation. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). Moesin is involved in mitotic spindle function through stabilizing cell shape and microtubules at the cell cortex. It is required for the formation of F-actin networks that mediate endosome biogenesis or maturation and transport through the degradative pathway.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031   5 VTRPDAVLmEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGESLWLNLRNRIS-QQMDGLAPYRLKLRVKFFVE 83
Cdd:cd17237   6 VTTMDAEL-EFAIQPNTTGKQLFDQVVKTIGLREVWFFGLQYQDTKGFSTWLKLNKKVTaQDVRKESPLLFKFRAKFYPE 84

Modified RING finger, HC subclass (C3HC5-type), found in neuralized-like protein NEURL1A, NEURL1B, and similar proteins; This subfamily includes Drosophila neuralized (D-neu) protein, and its two mammalian homologs, NEURL1A and NEURL1B. D-neu is a regulator of the developmentally important Notch signaling pathway. NEURL1A, also known as NEURL1, NEU, neuralized 1, or RING finger protein 67 (RNF67), is a mammalian homolog of D-neu. It functions as an E3 ubiquitin-protein ligase that directly interacts with and monoubiquitinates cytoplasmic polyadenylation element-binding protein 3 (CPEB3), an RNA binding protein and a translational regulator of local protein synthesis, which facilitates hippocampal plasticity and hippocampal-dependent memory storage. It also acts as a potential tumor suppressor that causes apoptosis and downregulates Notch target genes in medulloblastoma. NEURL1B, also known as neuralized-2 (NEUR2) or neuralized-like protein 3, is another mammalian homolog of D-neu protein. It functions as an E3 ubiquitin-protein ligase that interacts with and ubiquitinates Delta. Thus, it plays a role in the endocytic pathways for Notch signaling by working cooperatively with another E3 ligase, Mind bomb-1 (Mib1), in Delta endocytosis to hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-positive vesicles. Members of this subfamily contain two neuralized homology regions (NHRs) responsible for Neural-ligand interactions and a modified C3HC5-type RING-HC finger required for ubiquitin ligase activity. The C3HC5-type RING-HC finger is distinguished from typical C3HC4-type RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 30841031 387 CMACCEEEINSTFCPCGHTVCCESCAAQLQ----SCPVCRSRVEHVQHVY 432
Cdd:cd16647   4 CVICYERPVDTVLYRCGHMCMCYDCALQLKrrggSCPICRAPIKDVIKIY 53

FERM domain C-lobe of Protein tyrosine phosphatase non-receptor proteins 3 and 4 (PTPN4 and PTPN3); PTPN4 (also called PTPMEG, protein tyrosine phosphatase, megakaryocyte) is a cytoplasmic protein-tyrosine phosphatase (PTP) thought to play a role in cerebellar function. PTPMEG-knockout mice have impaired memory formation and cerebellar long-term depression. PTPN3/PTPH1 is a membrane-associated PTP that is implicated in regulating tyrosine phosphorylation of growth factor receptors, p97 VCP (valosin-containing protein, or Cdc48 in Saccharomyces cerevisiae), and HBV (Hepatitis B Virus) gene expression; it is mutated in a subset of colon cancers. PTPMEG and PTPN3/PTPH1 contains a N-terminal FERM domain, a middle PDZ domain, and a C-terminal phosphatase domain. PTP1/Tyrosine-protein phosphatase 1 from nematodes and a FERM_C repeat 1 from Tetraodon nigroviridis are also included in this cd. The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031 185 YGIEWHAVRDSEGQKLLIGVGPEGISICKEDFspinRIA-YPVVQMATQS--GKNVYLTVTKESGNSI--VLLFKMISTR 259
Cdd:cd13189   2 YGVELHSARDSNNLELQIGVSSAGILVFQNGI----RINtFPWSKIVKISfkRKQFFIQLRREPNESRdtILGFNMLSYR 77

                        90
                ....*....|....*..
gi 30841031 260 AASGLYRAITETHAFYR 276
Cdd:cd13189  78 ACKNLWKSCVEHHTFFR 94

RING finger, HC subclass, found in leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) and similar proteins; LRSAM1, also known as Tsg101-associated ligase (TAL), or RIFLE, is an E3 ubiquitin-protein ligase that physically associates with, and selectively ubiquitylates, Tsg101, an E2-like molecule that regulates vesicular trafficking processes in yeast and mammals. It regulates a Tsg101-associated complex responsible for the sorting of cargo into cytoplasm-containing vesicles that bud at the multivesicular body and at the plasma membrane. LRSAM1 is a multidomain protein containing an N-terminal leucine-rich repeat (LRR), followed by several recognizable motifs, including an ezrin-radixin-moezin (ERM) domain, a coiled-coil (CC) region, a SAM domain, and a C-terminal C3HC4-type RING-HC finger domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 30841031 387 CMACCEEEINSTFCPCGHTVCCESCAAQLQSCPVCRSRVEHV 428
Cdd:cd16515   4 CVVCMDAESQVIFLPCGHVCCCQTCSSSLSTCPLCRADITQR 45

RING finger, HC subclass, found in Arabidopsis thaliana protein XB3 homolog 5 (XBAT35) and similar proteins; XBAT35, also known as ankyrin repeat domain and RING finger-containing protein XBAT35, or RING-type E3 ubiquitin transferase XBAT35, has no E3 ubiquitin-protein ligase activity observed when associated with the E2 enzyme UBC8 in vitro. It contains a typical C3HC4-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 30841031 387 CMACCEEEINSTFCPCGHTVCCESCAAQLQ----SCPVCRSRVEHVQHVY 432
Cdd:cd23129   5 CVVCMDAPRDAVCVPCGHVAGCMSCLKALMqsspLCPICRAPVRQVIKVY 54

RING finger, HC subclass, found in RNA-binding protein MEX3C; MEX3C, also known as RING finger and KH domain-containing protein 2 (RKHD2), or RING finger protein 194 (RNF194), is an RNA-binding phosphoprotein that acts as a suppressor of chromosomal instability. It functions as an ubiquitin E3 ligase responsible for the post-transcriptional, HLA-A allotype-specific regulation of MHC class I molecules (MHC-I). It also modifies retinoic acid inducible gene-1 (RIG-I) in stress granules and plays a critical role in eliciting antiviral immune responses. Moreover, MEX3C plays an essential role in normal postnatal growth via enhancing the local expression of insulin-like growth factor 1 (IGF1) in bone. It may also be involved in metabolic regulation of energy balance. MEX3C contains two K homology (KH) domains that provide RNA-binding capacity, and a C-terminal C3HC4-type RING-HC finger. Like other MEX-3 family proteins, MEX3C shuttles between the nucleus and the cytoplasm via the CRM1-dependent export pathway.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 30841031 387 CMACCEEEINSTFCPCGHTVCCESCAAQ-----LQSCPVCRSRVEHVQHVY 432
Cdd:cd16722   4 CVICFENEVIAALVPCGHNLFCMECANKicekeTPSCPVCQTAVTQAIQIH 54

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in tyrosine-protein phosphatase non-receptor type 3 (PTPN3); PTPN3, also termed protein-tyrosine phosphatase H1 (PTP-H1), belongs to the non-transmembrane FERM-containing protein-tyrosine phosphatase (PTP) subfamily characterized by a conserved N-terminal FERM domain, a PDZ domain, and a C-terminal PTP catalytic domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). PTPN3 associates with the mitogen-activated protein kinase p38gamma (also known as MAPK12) to form a PTPN3-p38gamma complex that promotes Ras-induced oncogenesis. It may also act as a tumor suppressor in lung cancer through its modulation of epidermal growth factor receptor (EGFR) signaling. Moreover, PTPN3 shows sensitizing effect to anti-estrogens. It dephosphorylates the tyrosine kinase EGFR, disrupts its interaction with the nuclear estrogen receptor, and increases breast cancer sensitivity to small molecule tyrosine kinase inhibitors (TKIs). It also cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031   1 MLCYVTRPDAVLMEVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTGSKGES-LWLNLRNRISQQMDGLAPYRLKLRVK 79
Cdd:cd17193   2 VICNVHFLDGSVQSFKVNKQDTGQVLLDMAYNHLGLTEREYFGLQHNEDSVDSpRWLEPSKPIRKQLKGGFPCSLHFRVR 81

                ...
gi 30841031  80 FFV 82
Cdd:cd17193  82 FFI 84

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in tyrosine-protein phosphatase non-receptor type 13 (PTPN13) and similar proteins; This family includes tyrosine-protein phosphatase non-receptor type 13 (PTPN13), FERM and PDZ domain-containing protein 2 (FRMPD2), and FERM domain-containing proteins FRMD1 and FRMD6. All family members contain a FERM domain that is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30841031  14 EVEVEAKANGEDCLNQVCRRLGIIEVDYFGLQFTgSKGESLWLNLRNRIS-------------QQMDGLAPYRLKLRVKF 80
Cdd:cd17101  15 QVAVDVKTTVQDLFDQVCDHLGLQETELFGLAVL-KDGEYFFLDPDTKLSkyapkgwkseakkGLKGGKPVFTLYFRVKF 93

                ...
gi 30841031  81 FVE 83
Cdd:cd17101  94 YVD 96

RING finger, HC subclass, found in Arabidopsis thaliana SP1-like protein 2 (SPL2) and similar proteins; SPL2, also known as RING-type E3 ubiquitin transferase SPL2, acts as an E3 ubiquitin-protein ligase that mediates E2-dependent protein ubiquitination. SPL2 contains a typical C3HC4-type RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 30841031 383 EAMLCMACCEEEINSTFCPCGHTVCCESCAAQLQS-----CPVCR 422
Cdd:cd23145   2 DGELCVVCLLRRRRVAFIECGHRVCCELCARRVTReanprCPVCR 46

RING finger, HC subclass, found in RNA-binding protein MEX3D; MEX3D, also known as RING finger and KH domain-containing protein 1 (RKHD1), RING finger protein 193 (RNF193), or TINO, is an RNA-binding phosphoprotein that controls the stability of the transcripts coding for the anti-apoptotic protein BCL-2, and negatively regulates BCL-2 in HeLa cells. MEX3D contains two K homology (KH) domains that provide RNA-binding capacity, and a C-terminal C3HC4-type RING-HC finger. Like other MEX-3 family proteins, MEX3D shuttles between the nucleus and the cytoplasm via the CRM1-dependent export pathway.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 30841031 387 CMACCEEEINSTFCPCGHTVCCESCAAQL-----QSCPVCRSRVEHVQHVY 432
Cdd:cd16723  13 CVVCFESEVIAALVPCGHNLFCMECAIRIcgksePECPACHTPATQAIHIF 63

first RING finger, HC subclass, found in mind bomb 1 (MIB1) and similar proteins; MIB1, also known as DAPK-interacting protein 1 (DIP-1) or zinc finger ZZ type with ankyrin repeat domain protein 2, is a large, multi-domain E3 ubiquitin-protein ligase that promotes ubiquitination of the cytoplasmic tails of Notch ligands, and thus plays an essential role in controlling metazoan development by Notch signaling. It is also involved in Wnt/beta-catenin signaling and nuclear factor (NF)-kappaB signaling, and has been implicated in innate immunity, neuronal function, genomic stability, and cell death. MIB1 contains an MZM region with two Mib-Herc2 domains flanking a ZZ zinc finger, a REP region including two tandem Mib repeats, an ANK region that spans ankyrin repeats, and a RNG region consisting of three C3HC4-type RING-HC fingers. This model corresponds to the first RING-HC finger.

                        10        20        30
                ....*....|....*....|....*....|....*.
gi 30841031 387 CMACCEEEINSTFCPCGHTVCCESCAAQLQSCPVCR 422
Cdd:cd16724   3 CMVCSDMKRDTLFGPCGHIATCSLCSPRVKKCLICK 38

Modified RING finger, HC subclass (C3HC5-type), found in cell growth regulator with RING finger domain protein 1 (CGRRF1) and similar proteins; CGRRF1, also known as cell growth regulatory gene 19 protein (CGR19) or RING finger protein 197 (RNF197), functions as a novel biomarker to monitor endometrial sensitivity and response to insulin-sensitizing drugs, such as metformin, in the context of obesity. CGRRF1 contains a C-terminal modified C3HC5-type RING-HC finger, which is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

                        10        20        30
                ....*....|....*....|....*....|....*..
gi 30841031 386 LCMACCEEEINSTFCPCGHTVCCESCAAQLQSCPVCR 422
Cdd:cd16787   2 DCVVCQNAPVNRVLLPCRHACVCDECFKRLQRCPMCR 38

RING finger, HC subclass, found in RING domain ligase RGLG1, RGLG2 and similar proteins from plant; RGLG1 is a ubiquitously expressed E3 ubiquitin-protein ligase that interacts with UBC13 and, together with UBC13, catalyzes the formation of K63-linked polyubiquitin chains, which is involved in DNA damage repair. RGLG1 mediates the formation of canonical, K48-linked polyubiquitin chains that target proteins for degradation. It also regulates apical dominance by acting on the auxin transport proteins abundance. RGLG1 has overlapping functions with its closest sequelog, RGLG2. They both function as RING E3 ligases that interact with ethylene response factor 53 (ERF53) in the nucleus and negatively regulate the plant drought stress response. Members of this subfamily contain a Von Willebrand factor type A (vWA) domain and a C3HC4-type RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|.
gi 30841031 383 EAMLCMACCEEEINSTFcPCGHTVCCEsCAAQLQSCPVCRS 423
Cdd:cd16729   1 DDQLCPICLSNPKDMAF-GCGHQTCCE-CGQSLTHCPICRQ 39