FERM domain C-lobe of FERM domain containing 1 and 6 proteins; FRMD6 (also called willin and hEx/human expanded) is localized throughout the cytoplasm or along the plasma membrane. The Drosophilla protein Ex is a regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in organ size control and is tumor suppression by restricting proliferation and promoting apoptosis. Surprisingly, hEx is thought to function independently of the Hippo pathway. Instead it is hypothesized that hEx inhibits progression through the S phase of the cell cycle by upregulating p21(Cip1) and downregulating Cyclin A. It is also implicated in the progression of Alzheimer disease. Not much is known about FRMD1 to date. Both FRMD1 and FRMD6 contains a single FERM domain which 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 is a member of the PH superfamily. 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 2462610618 189 EDVPVHFFRLHKDKKEGRPTVILGLALRGVHIYQEVDRAPQLLYDLPWPHVGKLAFLGKKLEIQLDGlpAAQKLVYYTGC 268
Cdd:cd13185     1 EDLNAHLYRLRKSKKETPGSVLLGITAKGIQIYQESDGEQQLLRTFPWSNIGKLSFDRKKFEIRPEG--SLRKLTYYTSS 78

                          90       100
                  ....*....|....*....|....*....
gi 2462610618 269 TWRSRHLLHLLRASHQLHLRVRPTLQQLR 297
Cdd:cd13185    79 DEKSKYLLALCRETHQFSMAIQPRLSEIR 107

FERM domain C-lobe of FERM domain containing 1 and 6 proteins; FRMD6 (also called willin and hEx/human expanded) is localized throughout the cytoplasm or along the plasma membrane. The Drosophilla protein Ex is a regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in organ size control and is tumor suppression by restricting proliferation and promoting apoptosis. Surprisingly, hEx is thought to function independently of the Hippo pathway. Instead it is hypothesized that hEx inhibits progression through the S phase of the cell cycle by upregulating p21(Cip1) and downregulating Cyclin A. It is also implicated in the progression of Alzheimer disease. Not much is known about FRMD1 to date. Both FRMD1 and FRMD6 contains a single FERM domain which 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 is a member of the PH superfamily. 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 2462610618 189 EDVPVHFFRLHKDKKEGRPTVILGLALRGVHIYQEVDRAPQLLYDLPWPHVGKLAFLGKKLEIQLDGlpAAQKLVYYTGC 268
Cdd:cd13185     1 EDLNAHLYRLRKSKKETPGSVLLGITAKGIQIYQESDGEQQLLRTFPWSNIGKLSFDRKKFEIRPEG--SLRKLTYYTSS 78

                          90       100
                  ....*....|....*....|....*....
gi 2462610618 269 TWRSRHLLHLLRASHQLHLRVRPTLQQLR 297
Cdd:cd13185    79 DEKSKYLLALCRETHQFSMAIQPRLSEIR 107

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 2462610618    3 DVKATGRELFQQVCNVASIRDAQFFGLCVVR--NNEYIFMDLEQKLSKYFSKdwkkernegnekpRAPFVAFLRVQHYVE 80
Cdd:smart00295  17 DSSTTAEELLETVCRKLGIRESEYFGLQFEDpdEDLRHWLDPAKTLLDQDVK-------------SEPLTLYFRVKFYPP 83

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462610618   81 N-GRVISDHRARHLYYCHLKERVLRSQCAHREEAYFLLAACALQADLGEHRESAHAGRYFEPH-SYFPQWIITKRGIDYI 158
Cdd:smart00295  84 DpNQLKEDPTRLNLLYLQVRNDILEGRLPCPEEEALLLAALALQAEFGDYDEELHDLRGELSLkRFLPKQLLDSRKLKEW 163

                          170       180       190
                   ....*....|....*....|....*....|....*...
gi 2462610618  159 LRHMPTLHRERQGLSPKEAMLCFIQEACRLEDVPVHFF 196
Cdd:smart00295 164 RERIVELHKELIGLSPEEAKLKYLELARKLPTYGVELF 201

FERM C-terminal PH-like domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462610618 201 DKKEGrpTVILGLALRGVHIYQEVDRapqLLYDLPWPHVGKLAFLGKKLEIQLDGLPAAQKLVYYTGCTWRSRHLLHLLR 280
Cdd:pfam09380   1 DKEGT--DLWLGVSAKGILVYEDNNK---ILNLFPWREIRKISFKRKKFLIKLRDKSSEETLGFYTESSRACKYLWKLCV 75

                          90
                  ....*....|
gi 2462610618 281 ASHQLHLRVR 290
Cdd:pfam09380  76 EQHTFFRLRR 85

FERM domain C-lobe of FERM domain containing 1 and 6 proteins; FRMD6 (also called willin and hEx/human expanded) is localized throughout the cytoplasm or along the plasma membrane. The Drosophilla protein Ex is a regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in organ size control and is tumor suppression by restricting proliferation and promoting apoptosis. Surprisingly, hEx is thought to function independently of the Hippo pathway. Instead it is hypothesized that hEx inhibits progression through the S phase of the cell cycle by upregulating p21(Cip1) and downregulating Cyclin A. It is also implicated in the progression of Alzheimer disease. Not much is known about FRMD1 to date. Both FRMD1 and FRMD6 contains a single FERM domain which 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 is a member of the PH superfamily. 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 2462610618 189 EDVPVHFFRLHKDKKEGRPTVILGLALRGVHIYQEVDRAPQLLYDLPWPHVGKLAFLGKKLEIQLDGlpAAQKLVYYTGC 268
Cdd:cd13185     1 EDLNAHLYRLRKSKKETPGSVLLGITAKGIQIYQESDGEQQLLRTFPWSNIGKLSFDRKKFEIRPEG--SLRKLTYYTSS 78

                          90       100
                  ....*....|....*....|....*....
gi 2462610618 269 TWRSRHLLHLLRASHQLHLRVRPTLQQLR 297
Cdd:cd13185    79 DEKSKYLLALCRETHQFSMAIQPRLSEIR 107

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462610618  80 ENGRVISDHRARHLYYCHLKERVLRSQCAHREEAYFLLAACALQADLGEHRESAHAGRYFEPHSYFPQWIITKRGIDYIL 159
Cdd:pfam00373   1 DLELLLQDEVTRHLLYLQAKDDILEGRLPCSEEEALLLAALQLQAEFGDYQPSSHTSEYLSLESFLPKQLLRKMKSKELE 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 2462610618 160 RHMPTLHRERQGLSPKEAMLCFIQEACRLEDVPVHFF 196
Cdd:pfam00373  81 KRVLEAHKNLRGLSAEEAKLKYLQIAQSLPTYGVEFF 117

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM domain-containing protein 6 (FRMD6); FRMD6, also termed willin, expanded or expanded homolog, is a FERM domain-containing protein that plays a critical role in regulating both cell proliferation and apoptosis. It acts as a tumor suppressor of human breast cancer cells independently of the Hippo pathway. It also inhibits human glioblastoma growth and progression by negatively regulating activity of receptor tyrosine kinases. As an upstream component of the hippo signaling pathway, FRMD6 orchestrates mammalian peripheral nerve fibroblasts. FRMD6 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462610618   3 DVKATGRELFQQVCNVASIRDAQFFGLCVVRNNEYIFMDLEQKLSKYFSKDWKKERNEGNEKPRAPFVAFLRVQHYVENG 82
Cdd:cd17198    19 NVKTLCQELLVQVCDLLRLKDCHLFGLSVIQNNEHVYMELSQKLYKYCPKEWKKEASKGIDQFGPPMIVHFRVQYYVENG 98

FERM C-terminal PH-like domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462610618 201 DKKEGrpTVILGLALRGVHIYQEVDRapqLLYDLPWPHVGKLAFLGKKLEIQLDGLPAAQKLVYYTGCTWRSRHLLHLLR 280
Cdd:pfam09380   1 DKEGT--DLWLGVSAKGILVYEDNNK---ILNLFPWREIRKISFKRKKFLIKLRDKSSEETLGFYTESSRACKYLWKLCV 75

                          90
                  ....*....|
gi 2462610618 281 ASHQLHLRVR 290
Cdd:pfam09380  76 EQHTFFRLRR 85

FERM domain C-lobe; 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 2462610618 193 VHFFRLHKDKKEGRPtVILGLALRGVHIYQEVDRapQLLYDLPWPHVGKLAF-LGKKLEIQLDGLPAAQKLVYYTGCTwR 271
Cdd:cd00836     2 VEFFPVKDKSKKGSP-IILGVNPEGISVYDELTG--QPLVLFPWPNIKKISFsGAKKFTIVVADEDKQSKLLFQTPSR-Q 77

                          90
                  ....*....|....
gi 2462610618 272 SRHLLHLLRASHQL 285
Cdd:cd00836    78 AKEIWKLIVGYHRF 91

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2462610618   3 DVKATGRELFQQVCNVASIRDAQFFGLCVVRN-NEYIFMDLEQKLSKYFSKdwkkernegnekpRAPFVAFLRVQH 77
Cdd:cd01765    18 SKKATGQELFDKVCEKLNLLEKDYFGLFYEDNdGQKHWLDLDKKISKQLKR-------------SGPYQFYFRVKF 80

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM and PDZ domain-containing protein 2 (FRMPD2); FRMPD2, also termed PDZ domain-containing protein 4 (PDZK4), or PDZ domain-containing protein 5C (PDZD5C), is a potential scaffold protein involved in basolateral membrane targeting in epithelial cells. It interacts with nucleotide-binding oligomerization domain-2 (NOD2) through leucine-rich repeats and forms a complex with the membrane-associated protein ERBB2IP. FRMPD2 contains an N-terminal KIND domain, a FERM domain and three PDZ domains. 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2462610618   3 DVKATGRELFQQVCNVASIRDAQFFGLCVVRNNEYIFMDLEQKLSKYFSKDWKKERNEgnEKPRAPFVAFLRVQHYVEN 81
Cdd:cd17196    19 DIKSRVRDVFNMVVAFANLVEHFYFGLAYMKGKEFFFLDHETKLHKVAPEGWKDQSKK--KTSIVNFTLFLRIKFFVDN 95

FERM domain C-lobe/F3 of the ERM family; The ERM family includes ezrin, radixin, moesin and merlin. They are composed of a N-terminal FERM (ERM) domain (also called N-ERMAD (N-terminal ERM association domain)), a coiled coil region (CRR), and a C-terminal domain CERMAD (C-terminal ERM association domain) which has an F-actin-binding site (ABD). Two actin-binding sites have been identified in the middle and N-terminal domains. Merlin is structurally similar to the ERM proteins, but instead of an actin-binding domain (ABD), it contains a C-terminal domain (CTD), just like the proteins from the 4.1 family. Activated ezrin, radixin and moesin are thought to be involved in the linking of actin filaments to CD43, CD44, ICAM1-3 cell adhesion molecules, various membrane channels and receptors, such as the Na+/H+ exchanger-3 (NHE3), cystic fibrosis transmembrane conductance regulator (CFTR), and the beta2-adrenergic receptor. The ERM proteins 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 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 of ERM 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 2462610618 200 KDKKeGRPtVILGLALRGVHIYQEVDR-APQLLYdlPWPHVGKLAFLGKKLEIQLDGLpAAQKLVYYTGCTWRSRHLLHL 278
Cdd:cd13194    10 KNKK-GTD-LWLGVDALGLNIYEPDNKlTPKIGF--PWSEIRNISFNDKKFVIKPIDK-KAPDFVFYSPRLRINKRILDL 84

                          90
                  ....*....|..
gi 2462610618 279 LRASHQLHLRVR 290
Cdd:cd13194    85 CMGNHELYMRRR 96

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in Ezrin and similar proteins; Ezrin, also termed cytovillin, or villin-2, or p81, 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). Ezrin is a tyrosine kinase substrate that functions as a cross-linker between actin cytoskeleton and plasma membrane. It has been implicated in the regulation of the proliferation, apoptosis, adhesion, invasion, metastasis and angiogenesis of cancer cells.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2462610618   7 TGRELFQQVCNVASIRDAQFFGLCVVRNNEYI-FMDLEQKLSkyfSKDWKKErNEGNEKPRAPF 69
Cdd:cd17239    23 TGKQLFDQVVKTIGLREVWYFGLQYVDNKGFPtWLKLDKKVS---AQEVRKE-NPLQFKFRAKF 82

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in merlin and similar proteins; Merlin, also termed moesin-ezrin-radixin-like protein, or neurofibromin-2 (NF2), or Schwannomerlin, or Schwannomin, 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, merlin however lacks the typical actin-binding motif in the C-tail. 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). Merlin plays vital roles in controlling proper development of organ sizes by specifically binding to a large number of target proteins localized both in cytoplasm and nuclei. Merlin may function as a tumor suppressor that functions upstream of the core Hippo pathway kinases Lats1/2 (Wts in Drosophila) and Mst1/2 (Hpo in Drosophila), as well as the nuclear E3 ubiquitin ligase DDB1-and-Cullin 4-associated Factor 1 (DCAF1)-associated cullin 4-Roc1 ligase, CRL4(DCAF1). Merlin may also has a tumor suppressor function in melanoma cells, the inhibition of the proto-oncogenic Na(+)/H(+) exchanger isoform 1 (NHE1) activity.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2462610618   3 DVKATGRELFQQVCNVASIRDAQFFGLCVVRNNEYIF---MD---LEQKLSK 48
Cdd:cd17186    19 EMKWKGKDLFDLVCRTIGLRETWYFGLQYTDSKGTVAwlkMDkkvLDQDVPK 70