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 1178431708 404 YGVDLHHAKDSEGVDIKLGVCANGLLIYKDRLRINRFAWPKILKISYKRSNFYIKVRPAELEQFESTIGFKLPNHRAAKR 483
Cdd:cd13184     1 YGVDLHPAKDSEGVDIMLGVCSSGLLVYRDRLRINRFAWPKVLKISYKRNNFYIKIRPGEFEQYETTIGFKLPNHRAAKR 80

                          90
                  ....*....|....
gi 1178431708 484 LWKVCVEHHTFYRL 497
Cdd:cd13184    81 LWKVCVEHHTFFRL 94

FERM adjacent (FA); This region is found adjacent to Band 4.1 / FERM domains (pfam00373) in a subset of FERM containing protein. The region has been hypothesized to play a role in regulatory adaptation, based on similarity to other protein kinase substrates.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1178431708 507 KFLTLGSKFRYSGRTQAQTRQASTLIDRPAPHFERTSSKRVSRS 550
Cdd:pfam08736   1 KFFSLGSKFRYSGRTQKQTVEDSSEILRPQPEFERSPSKRYPSR 44

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 1178431708 404 YGVDLHHAKDSEGVDIKLGVCANGLLIYKDRLRINRFAWPKILKISYKRSNFYIKVRPAELEQFESTIGFKLPNHRAAKR 483
Cdd:cd13184     1 YGVDLHPAKDSEGVDIMLGVCSSGLLVYRDRLRINRFAWPKVLKISYKRNNFYIKIRPGEFEQYETTIGFKLPNHRAAKR 80

                          90
                  ....*....|....
gi 1178431708 484 LWKVCVEHHTFYRL 497
Cdd:cd13184    81 LWKVCVEHHTFFRL 94

4.1 protein C-terminal domain (CTD); At the C-terminus of all known 4.1 proteins is a sequence domain unique to these proteins, known as the C-terminal domain (CTD). Mammalian CTDs are associated with a growing number of protein-protein interactions, although such activities have yet to be associated with invertebrate CTDs. Mammalian CTDs are generally defined by sequence alignment as encoded by exons 18-21. Comparison of known vertebrate 4.1 proteins with invertebrate 4.1 proteins indicates that mammalian 4.1 exon 19 represents a vertebrate adaptation that extends the sequence of the CTD with a Ser/Thr-rich sequence. The CTD was first described as a 22/24-kDa domain by chymotryptic digestion of erythrocyte 4.1 (4.1R). CTD is thought to represent an independent folding structure which has gained function since the divergence of vertebrates from invertebrates.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 822 KEVPIVQTETKTITYESPQIDGGAGGDSGTLLTAQTITSESVSTTTTTHITKTVKGGISETRIEKRIVITGDGDIDHDQA 901
Cdd:pfam05902   1 KEVPIVHTETKTITYESSQVDGRGDSDPGVLVSAQTITSETQSTTTTTHITKTVKGGISETRIEKRIVITGDADIDHDQA 80

                          90       100
                  ....*....|....*....|....*..
gi 1178431708 902 LAQAIREAREQHPDMSVTRVVVHKETE 928
Cdd:pfam05902  81 LAQAIKEAKEQHPDMSVTKVVVHKETE 107

FERM C-terminal PH-like domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 413 DSEGVDIKLGVCANGLLIYKDRLRI-NRFAWPKILKISYKRSNFYIKVRpaeLEQFESTIGFKLPNHRAAKRLWKVCVEH 491
Cdd:pfam09380   1 DKEGTDLWLGVSAKGILVYEDNNKIlNLFPWREIRKISFKRKKFLIKLR---DKSSEETLGFYTESSRACKYLWKLCVEQ 77

                  ....*.
gi 1178431708 492 HTFYRL 497
Cdd:pfam09380  78 HTFFRL 83

MAEBL; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708    9 SEVKKDSSQLGTDATKEKPKEVAENQQNQSSDpEEEKGSQPPPAAESQSSLRRQKREKETSESRGISRFIPPWLKKQKSY 88
Cdd:PTZ00121  1530 AEEAKKADEAKKAEEKKKADELKKAEELKKAE-EKKKAEEAKKAEEDKNMALRKAEEAKKAEEARIEEVMKLYEEEKKMK 1608

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708   89 TLVVAKDGGDKKEPTQAVVEEQVLDKEEPLPEEQRQAKGDAEEMAQKKQEIKVEVKEEKPSVSKEEKpsvsKVEmqptEL 168
Cdd:PTZ00121  1609 AEEAKKAEEAKIKAEELKKAEEEKKKVEQLKKKEAEEKKKAEELKKAEEENKIKAAEEAKKAEEDKK----KAE----EA 1680

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1178431708  169 VSKEREEKVKETQEDKLEggAAKRETKEVQTNELKAEKASQKVTKKTKTVQCKV 222
Cdd:PTZ00121  1681 KKAEEDEKKAAEALKKEA--EEAKKAEELKKKEAEEKKKAEELKKAEEENKIKA 1732

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 1178431708 404 YGVDLHHAKDSEGVDIKLGVCANGLLIYKDRLRINRFAWPKILKISYKRSNFYIKVRPAELEQFESTIGFKLPNHRAAKR 483
Cdd:cd13184     1 YGVDLHPAKDSEGVDIMLGVCSSGLLVYRDRLRINRFAWPKVLKISYKRNNFYIKIRPGEFEQYETTIGFKLPNHRAAKR 80

                          90
                  ....*....|....
gi 1178431708 484 LWKVCVEHHTFYRL 497
Cdd:cd13184    81 LWKVCVEHHTFFRL 94

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 1178431708 217 TVQCKVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLRNLPWLFTFNVKF 296
Cdd:cd17106     1 SQQCKVLLLDGTEYTCEVEKRAKGQVLFDKVCEHLNLLEKDYFGLTYRDAQDQKNWLDPAKEIKKQIRSGPWLFSFNVKF 80

                  ....
gi 1178431708 297 YPPD 300
Cdd:cd17106    81 YPPD 84

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 1178431708 220 CKVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLRNLPWLFTFNVKFYPP 299
Cdd:cd17201     4 CKVTLLDGSEYECEVEKHARGQVLFDTVCEHLNLLEKDYFGLTFCDTESQKNWLDPSKEIKKQIRSGPWHFAFTVKFYPP 83

                  .
gi 1178431708 300 D 300
Cdd:cd17201    84 D 84

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in erythrocyte membrane protein band 4.1 (EPB41) and similar proteins; EPB41, also termed protein 4.1 (P4.1), or 4.1R, or Band 4.1, or EPB4.1, belongs to the skeletal protein 4.1 family that is involved in cellular processes such as cell adhesion, migration and signaling. EPB41 is a widely expressed cytoskeletal phosphoprotein that stabilizes the spectrin-actin cytoskeleton and anchors the cytoskeleton to the cell membrane. EPB41 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 1178431708 219 QCKVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLRNLPWLFTFNVKFYP 298
Cdd:cd17105     2 HCKVSLLDDTVYECEVEKHAKGQDLFKKVCEHLNLLEEDYFGLAIWDSPTSKTWLDPAKEIKKQVHGGPWEFTFNVKFYP 81

                  ..
gi 1178431708 299 PD 300
Cdd:cd17105    82 PD 83

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 299 PDPSQLTEDITRYFLCLQLRQDIASGRLPCSFVTHALLGSYTLQAELGDYDPEEHGSIDLSEFQFAPTQ------TKELE 372
Cdd:pfam00373   1 DLELLLQDEVTRHLLYLQAKDDILEGRLPCSEEEALLLAALQLQAEFGDYQPSSHTSEYLSLESFLPKQllrkmkSKELE 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1178431708 373 EKVAELHKTHRGLSPAQADSQFLENAKRLSMYGVDLH 409
Cdd:pfam00373  81 KRVLEAHKNLRGLSAEEAKLKYLQIAQSLPTYGVEFF 117

FERM domain C-lobe of FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins; Members here include FARP1 (also called Chondrocyte-derived ezrin-like protein; PH domain-containing family C member 2), FARP2 (also called FIR/FERM domain including RhoGEF; FGD1-related Cdc42-GEF/FRG), and FRMD7(FERM domain containing 7). FARP1 and FARP2 are members of the Dbl family guanine nucleotide exchange factors (GEFs) which are upstream positive regulators of Rho GTPases. FARP1 has increased expression in differentiated chondrocytes. FARP2 is thought to regulate neurite remodeling by mediating the signaling pathways from membrane proteins to Rac. It is found in brain, lung, and testis, as well as embryonic hippocampal and cortical neurons. These members are composed of a N-terminal FERM domain, a proline-rich (PR) domain, Dbl-homology (DH), and two C-terminal PH domains. Other members in this family do not contain the DH domains such as the Human FERM domain containing protein 7 and Caenorhabditis elegans CFRM3, both of which have unknown functions. They contain an N-terminal FERM domain, a PH domain, followed by a FA (FERM adjacent) 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 1178431708 396 ENAKRLSMYGVDLHHAKDSEGVDIKLGVCANGLLIYKDRLRINRFAWPKILKISYKRSNFYIKVRPAELEQFESTIGFKL 475
Cdd:cd13193     1 ETARRCELYGIRLHPAKDREGVKLNLAVAHMGILVFQGFTKINTFSWAKIRKLSFKRKRFLIKLHPEAYGSYKDTVEFSF 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1178431708 476 PNHRAAKRLWKVCVEHHTFYRLVSPEQPP--KAKFLTLGSKF 515
Cdd:cd13193    81 ESRNECKSFWKKCIEHHAFFRCSEVPKPPspKLRLFSRGSSF 122

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 1178431708 218 VQCKVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLRN-LPWLFTFNVKF 296
Cdd:cd01765     1 ISCRVRLLDGTELTLEVSKKATGQELFDKVCEKLNLLEKDYFGLFYEDNDGQKHWLDLDKKISKQLKRsGPYQFYFRVKF 80

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 219 QCKVTLLDGTEYS-CDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLRNL-PWLFTFNVKF 296
Cdd:cd17102     2 KCTIRLLDDSEVIcCEFKKDTKGQFLLDYVCNYLNLLEKDYFGLRYVDTEKQRHWLDPNKSIYKQLKGVpPYVLCFRVKF 81

                  .
gi 1178431708 297 Y 297
Cdd:cd17102    82 Y 82

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 218 VQCKVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLR-NLPWLFTFNVKF 296
Cdd:cd17108     1 IQCKVILLDGTDLSIELPKKAKGQELYEQVFYHLDLIEKDYFGLQFMDAAQVQHWLDPTKKIKKQVKiGPPYTLRFRVKF 80

                  .
gi 1178431708 297 Y 297
Cdd:cd17108    81 Y 81

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 1178431708 222 VTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLR 284
Cdd:pfam09379   1 VRLLDGTVLEFDVQPKATGQVLLDQVCNHLNLKEKDYFGLQFLDDNGEHRWLDLSKRLSKQAP 63

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 218 VQCKVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLR-NLPWLFTFNVKF 296
Cdd:cd17205     3 ITCRVSLLDGTDVSVDLPKKAKGQELFEQIMYHLDLIEKDYFGLRFMDSAQVAHWLDVTKSIKKQVKiGPPYCLHLRVKF 82

                  .
gi 1178431708 297 Y 297
Cdd:cd17205    83 Y 83

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM, ARH/RhoGEF and pleckstrin domain-containing protein 2 (FARP2) and similar proteins; 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. FARP2 contains a FERM domain, a Dbl-homology (DH) domain and two pleckstrin homology (PH) 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 218 VQCKVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLRN-LPWLFTFNVKF 296
Cdd:cd17190     1 LQLRVKLLDNTTEPLEIEPKADGQALLSQVFKRLNLVESDYFGLEFQNSQSNWIWLEPMKLIVKQVRRpKNTKLRLAVKF 80

                  ....*
gi 1178431708 297 YPPDP 301
Cdd:cd17190    81 FPPDP 85

FERM adjacent (FA); This region is found adjacent to Band 4.1 / FERM domains (pfam00373) in a subset of FERM containing protein. The region has been hypothesized to play a role in regulatory adaptation, based on similarity to other protein kinase substrates.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1178431708 507 KFLTLGSKFRYSGRTQAQTRQASTLIDRPAPHFERTSSKRVSRS 550
Cdd:pfam08736   1 KFFSLGSKFRYSGRTQKQTVEDSSEILRPQPEFERSPSKRYPSR 44

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in tyrosine-protein phosphatase non-receptor type 4 (PTPN4); PTPN4, also termed protein-tyrosine phosphatase MEG1 (MEG) or PTPase-MEG1, 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). PTPN4 protects cells against apoptosis. It associates with the mitogen-activated protein kinase p38gamma (also known as MAPK12) to form a PTPN4-p38gamma complex that promotes cellular signaling, preventing cell death induction. It also inhibits tyrosine phosphorylation and subsequent cytoplasm translocation of TRIF-related adaptor molecule (TRAM, also known as TICAM2), resulting in the disturbance of TRAM-TRIF interaction. Moreover, PTPN4 negatively regulates cell proliferation and motility through dephosphorylation of CrkI.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 218 VQCKVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGL-LFQESPEQKNWLDPAKEIKRQL-RNLPWLFTFNVK 295
Cdd:cd17194     2 VVCNILLLDNTVQAFKVNKHDQGQVLLDLVFKHLDLTERDYFGLqLADDSTDNPRWLDPNKPIRKQLkRGSPHNLNFRVK 81

                  ..
gi 1178431708 296 FY 297
Cdd:cd17194    82 FF 83

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 221 KVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLRNLPWL-FTFNVKFYPP 299
Cdd:cd17188     5 KVQFLDDSQKVFVVDQKSTGKDLFNMSCSHLNLVEKEYFGLEFRNHAGNNVWLELLKPITKQIKNPKELiFKFTVKFFPV 84

                  ..
gi 1178431708 300 DP 301
Cdd:cd17188    85 DP 86

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 1178431708 404 YGVDLHHAKDSEGVDIKLGVCANGLLIYKDRLR-INRFAWPKILKISYKRSNFYIKVRpaeLEQFEST-IGFKLPNHRAA 481
Cdd:cd13195     1 YGVEFFEVRNIEGQKLLIGVGPHGITICNDDFEvIERIPYTAIQMATSSGRVFTLTYL---SDDGSVKvLEFKLPSTRAA 77

                          90
                  ....*....|....*
gi 1178431708 482 KRLWKVCVEHHTFYR 496
Cdd:cd13195    78 SGLYRAITEKHAFYR 92

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in the ERM family proteins; The ezrin-radixin-moesin (ERM) family includes a group of closely related cytoskeletal proteins that play 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). Merlin, which is highly related to the members of the ezrin, radixin, and moesin (ERM) protein family that are directly attached to and functionally linked with NHE1, is included in this family.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 218 VQCKVTLLDGT-EYSCdlEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLR--NLPWLFTFNV 294
Cdd:cd17097     1 INVRVTTMDAElEFSI--KPKAKGRELFDLVCRTIGLRETWYFGLQYENKKGRVAWLKPDKKVLTQDVskNNTLKFFFLV 78

                  ....
gi 1178431708 295 KFYP 298
Cdd:cd17097    79 KFYP 82

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in tyrosine-protein phosphatase non-receptors PTPN14, PTPN21, and similar proteins; This family includes tyrosine-protein phosphatase non-receptors PTPN14 and PTPN21, both of which are protein-tyrosine phosphatase (PTP). They belong to the FERM family of PTPs characterized by a conserved N-terminal FERM domain and a C-terminal PTP catalytic domain with an intervening sequence containing an acidic region and a putative SH3 domain-binding sequence. 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). PTPN14 plays a role in the nucleus during cell proliferation. PTPN21 interacts with a Tec tyrosine kinase family member, the epithelial and endothelial tyrosine kinase (Etk, also known as Bmx), modulates Stat3 activation, and plays a role in the regulation of cell growth and differentiation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 221 KVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLRNL---PWLFtFNVKFY 297
Cdd:cd17099     7 RIQLLDNTVLECTLSPESTGQDCLEYVAQRLELREIEYFGLRYVNKKGQLRWVDLEKPLKKQLDKHahePLLY-FGVMFY 85

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 216 KTVQCKVTLLDGT-EYSCDLEkhAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQ--LRNLPWLFTF 292
Cdd:cd17186     1 KTFTVRIVTMDAEmEFNCEMK--WKGKDLFDLVCRTIGLRETWYFGLQYTDSKGTVAWLKMDKKVLDQdvPKEEPVTFHF 78

                  ....*.
gi 1178431708 293 NVKFYP 298
Cdd:cd17186    79 LAKFYP 84

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in tyrosine-protein phosphatase non-receptor type 14 (PTPN14) and similar proteins; PTPN14, also termed protein-tyrosine phosphatase pez, or PTPD2, or PTP36, is a widely expressed non-transmembrane cytosolic protein tyrosine phosphatase (PTP). It belongs to the FERM family of PTPs characterized by a conserved N-terminal FERM domain and a C-terminal PTP catalytic domain with an intervening sequence containing an acidic region and a putative SH3 domain-binding sequence. 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). PTPN14 plays a role in the nucleus during cell proliferation. It forms a complex with Kibra and LATS1 proteins and negatively regulates the key Hippo pathway protein Yes-associated protein (YAP) oncogenic function by controlling its localization. It specifically regulates p130 Crk-associated substrate (p130Cas) phosphorylation at tyrosine residue 128 (Y128) in colorectal cancer (CRC) cells. Moreover, PTPN14 may be a critical enzyme in regulating endothelial cell function. It plays a crucial role in organogenesis by inducing transforming growth factor beta (TGFbeta) and epithelial-mesenchymal transition (EMT). It also acts as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. It regulates the lymphatic function and choanal development through the interaction with the vascular endothelial growth factor receptor 3 (VEGFR3), a receptor tyrosine kinase essential for lymphangiogenesis. Furthermore, PTPN14 functions as a regulator of cell motility through its action on cell-cell adhesion. Beta-Catenin, a central component of adherens junctions, has been identified as a PTPN14 substrate. PTPN14 works as a novel sperm-motility biomarker and a potential mitochondrial protein.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 221 KVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLR---NLPWLFtFNVKFY 297
Cdd:cd17191     7 RIRLLDSNVIECTLSVESTGQECLEAVAQRLELRETHYFGLWFLSKSQQARWVELEKPLKKQLDkfaNEPLLF-FGVMFY 85

                  ..
gi 1178431708 298 PP 299
Cdd:cd17191    86 VP 87

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 1178431708 217 TVQCKVTLLDGtEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQ--LRNLPWLFTFNV 294
Cdd:cd17237     1 TISVRVTTMDA-ELEFAIQPNTTGKQLFDQVVKTIGLREVWFFGLQYQDTKGFSTWLKLNKKVTAQdvRKESPLLFKFRA 79

                  ....
gi 1178431708 295 KFYP 298
Cdd:cd17237    80 KFYP 83

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM domain-containing protein 4B (FRMD4B); FRMD4B, also termed GRP1-binding protein GRSP1, interacts with the coil-coil domain of ARF exchange factor GRP1 to form the Grsp1-Grp1 complex that co-localizes with cortical actin rich regions in response to stimulation of CHO-T cells with insulin or epidermal growth factor (EGF). FRMD4B contains a FERM protein interaction domain as well as two coiled coil domains and may therefore function as a scaffolding protein. 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 1178431708 220 CKVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLdpakEIKRQL-------RNLPWLFTF 292
Cdd:cd17200     5 CQVHLLDDRKLELLVQPKLLSRELLDLVASHFNLKEKEYFGITFIDDTGQSNWL----QLDHRVldhdlpkKSGPVTLYF 80

                  ....*
gi 1178431708 293 NVKFY 297
Cdd:cd17200    81 AVRFY 85

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in tyrosine-protein phosphatase non-receptor type 21 (PTPN21) and similar proteins; PTPN21, also termed protein-tyrosine phosphatase D1 (PTPD1), is a cytosolic non-receptor protein-tyrosine phosphatase (PTP) that belongs to the FERM family of PTPs characterized by a conserved N-terminal FERM domain and a C-terminal PTP catalytic domain with an intervening sequence containing an acidic region and a putative SH3 domain-binding sequence. 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). PTPN21 interacts with a Tec tyrosine kinase family member, the epithelial and endothelial tyrosine kinase (Etk, also known as Bmx), modulates Stat3 activation, and plays a role in the regulation of cell growth and differentiation. It also associates with and activates Src tyrosine kinase, and directs epidermal growth factor (EGF)/Src signaling to the nucleus through activating ERK1/2- and Elk1-dependent gene transcription. PTPD1-Src complex interacts a protein kinase A-anchoring protein AKAP121 to forms a PTPD1-Src-AKAP121 complex, which is required for efficient maintenance of mitochondrial membrane potential and ATP oxidative synthesis. As a novel component of the endocytic pathway, PTPN21 supports EGF receptor stability and mitogenic signaling in bladder cancer cells. Moreover, PTPD1 regulates focal adhesion kinase (FAK) autophosphorylation and cell migration through modulating Src-FAK signaling at adhesion sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1178431708 221 KVTLLDGTEYSCDLEKHAKGQVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLRNL---PWLFtFNVKFY 297
Cdd:cd17192     7 RIQLLNNEFVEFTLSVESTGQECLEAVAQRLELREITYFSLWYYNKQNQQRWVDLEKPLKKQLDKYalePTVY-FGVVFY 85