C-terminal domain of adaptor protein (AP) complexes medium mu subunits and its homologs (MHD); This family corresponds to the C-terminal domain of heterotetrameric AP complexes medium mu subunits and its homologs existing in monomeric stonins, delta-subunit of the heteroheptameric coat protein I (delta-COPI), a protein encoded by a pro-death gene referred as MuD (also known as MUDENG, mu-2 related death-inducing gene), an endocytic adaptor syp1, the mammalian FCH domain only proteins (FCHo1/2), SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1), and related proteins. AP complexes participate in the formation of intracellular coated transport vesicles and select cargo molecules for incorporation into the coated vesicles in the late secretory and endocytic pathways. Stonins have been characterized as clathrin-dependent AP-2 mu chain related factors and may act as cargo-specific sorting adaptors in endocytosis. Coat protein complex I (COPI)-coated vesicles function in the early secretory pathway. They mediate the retrograde transport from the Golgi to the ER, and intra-Golgi transport. MuD is distantly related to the C-terminal domain of mu2 subunit of AP-2. It is able to induce cell death by itself and plays an important role in cell death in various tissues. Syp1 represents a novel type of endocytic adaptor protein that participates in endocytosis, promotes vesicle tabulation, and contributes to cell polarity and stress responses. It shares the same domain architecture with its two ubiquitously expressed mammalian counterparts, FCHo1/2, which represent key initial proteins ultimately controlling cellular nutrient uptake, receptor regulation, and synaptic vesicle retrieval. They bind specifically to the plasma membrane and recruit the scaffold proteins eps15 and intersectin, which subsequently engage the adaptor complex AP2 and clathrin, leading to coated vesicle formation. Another mammalian neuronal-specific protein SGIP1 does have a C-terminal MHD and has been classified into this family as well. It is an endophilin-interacting protein that plays an obligatory role in the regulation of energy homeostasis. It is also involved in clathrin-mediated endocytosis by interacting with phospholipids and eps15.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871 485 PIATAFTEYVHAYFRGH-SPSCLARVTGELTMTFPAGIVRVFSGTPPPPVLSFRLVHTTAIEHFQPNADLLFSDPSQSDP 563
Cdd:cd09268     1 PVAAAFTEYVHAYFRGGaLEGCLLRITGELTMSFPAGILRVFASTPTPPVLSFRLVHTSHVEHFAPNSELLFSDPSQSDP 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1858900871 564 ETKDFWLNMAALTEALQRQAEQNPTASYYNVVLLRYQ--EPGGEAAHLE-ASRCVRG 617
Cdd:cd09268    81 NTKDFWLNMPALTSYLQRMAEQNPQASYYNVTLLKYQvsKSGPSAAPLYlSATWQCG 137

mu-homology domain (MHD) of F-BAR domain-containing Fer/Cip4 homology domain-only protein 1 (FCH domain only 1 or FCHo1, also known as KIAA0290) and similar proteins; This family corresponds to the MHD found in ubiquitously expressed mammalian membrane-sculpting FCHo1 and similar proteins. FCHo1 represents a key initial protein that ultimately controls cellular nutrient uptake, receptor regulation, and synaptic vesicle retrieval. It is required for plasma membrane clathrin-coated vesicle (CCV) budding and marks sites of CCV formation. It binds specifically to the plasma membrane and recruits the scaffold proteins eps15 and intersectin, which subsequently engage the adaptor complex AP2 and clathrin, leading to coated vesicle formation. FCHo1 contains an N-terminal EFC/F-BAR domain, a proline-rich domain (PRD) in the middle region, and a C-terminal MHD. The crescent-shaped EFC/F-BAR domain can form an antiparallel dimer structure that binds PtdIns(4,5)P2-enriched membranes and can polymerize into rings to generate membrane tubules. The MHD is structurally related to the cargo-binding mu2 subunit of adaptor complex 2 (AP-2) and is responsible for the binding of eps15 and intersectin. Unlike other F-BAR domain containing proteins, FCHo1 has neither the Src homology 3 (SH3) domain nor any other known domain for interaction with dynamin and actin cytoskeleton. However, it can periodically accumulate at the budding site of clathrin. FCHo1 may utilize a unique action mode for vesicle formation as compared with other F-BAR proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871 485 PIATAFTEYVHAYFRGH-SPSCLARVTGELTMTFPAGIVRVFSGTPPPPVLSFRLVHTTAIEHFQPNADLLFSDPSQSDP 563
Cdd:cd09268     1 PVAAAFTEYVHAYFRGGaLEGCLLRITGELTMSFPAGILRVFASTPTPPVLSFRLVHTSHVEHFAPNSELLFSDPSQSDP 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1858900871 564 ETKDFWLNMAALTEALQRQAEQNPTASYYNVVLLRYQ--EPGGEAAHLE-ASRCVRG 617
Cdd:cd09268    81 NTKDFWLNMPALTSYLQRMAEQNPQASYYNVTLLKYQvsKSGPSAAPLYlSATWQCG 137

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of FCH domain Only proteins; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. Proteins in this group have been named FCH domain Only (FCHO) proteins. Vertebrates have two members, FCHO1 and FCHO2. These proteins contain an F-BAR domain and a C-terminal domain of unknown function named SAFF which is also present in endophilin interacting protein 1. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871   1 MAKLSKLASNGTPMGTFAPLWEVFRVSSDKLALCHLELTRKLQDLIKDVLRYGEEQLKTHKKCKEEVVSTLDAVQVLSGV 80
Cdd:cd07648    42 LNKLAKQASNSSQLGTFAPLWLVLRVSTEKLSELHLQLVQKLQELIKDVQKYGEEQHKKHKKVKEEESGTAEAVQAIQTT 121

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871  81 SQLLPKSRENYLNRCMDQERLRRESTSQKEMDKAETKTKKAAESLRRSVEKYNSARADFEQKMLDSALRFQAMEETHLRH 160
Cdd:cd07648   122 TAALQKAKEAYHARCLELERLRRENASPKEIEKAEAKLKKAQDEYKALVEKYNNIRADFETKMTDSCKRFQEIEESHLRQ 201

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1858900871 161 MKALLGSYAHSVEDTHVQIGQVHEEFKQNIENVSVEMLLRKFAESKGTGREKPGPLDFE 219
Cdd:cd07648   202 MKEFLASYAEVLSENHSAVGQVHEEFKRQVDELTVDKLLRQFVESKGTGTEKPELIEFE 260

mu-homology domain (MHD) of F-BAR domain-containing Fer/Cip4 homology domain-only protein 1 (FCH domain only 1 or FCHo1, also known as KIAA0290) and similar proteins; This family corresponds to the MHD found in ubiquitously expressed mammalian membrane-sculpting FCHo1 and similar proteins. FCHo1 represents a key initial protein that ultimately controls cellular nutrient uptake, receptor regulation, and synaptic vesicle retrieval. It is required for plasma membrane clathrin-coated vesicle (CCV) budding and marks sites of CCV formation. It binds specifically to the plasma membrane and recruits the scaffold proteins eps15 and intersectin, which subsequently engage the adaptor complex AP2 and clathrin, leading to coated vesicle formation. FCHo1 contains an N-terminal EFC/F-BAR domain, a proline-rich domain (PRD) in the middle region, and a C-terminal MHD. The crescent-shaped EFC/F-BAR domain can form an antiparallel dimer structure that binds PtdIns(4,5)P2-enriched membranes and can polymerize into rings to generate membrane tubules. The MHD is structurally related to the cargo-binding mu2 subunit of adaptor complex 2 (AP-2) and is responsible for the binding of eps15 and intersectin. Unlike other F-BAR domain containing proteins, FCHo1 has neither the Src homology 3 (SH3) domain nor any other known domain for interaction with dynamin and actin cytoskeleton. However, it can periodically accumulate at the budding site of clathrin. FCHo1 may utilize a unique action mode for vesicle formation as compared with other F-BAR proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871 485 PIATAFTEYVHAYFRGH-SPSCLARVTGELTMTFPAGIVRVFSGTPPPPVLSFRLVHTTAIEHFQPNADLLFSDPSQSDP 563
Cdd:cd09268     1 PVAAAFTEYVHAYFRGGaLEGCLLRITGELTMSFPAGILRVFASTPTPPVLSFRLVHTSHVEHFAPNSELLFSDPSQSDP 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1858900871 564 ETKDFWLNMAALTEALQRQAEQNPTASYYNVVLLRYQ--EPGGEAAHLE-ASRCVRG 617
Cdd:cd09268    81 NTKDFWLNMPALTSYLQRMAEQNPQASYYNVTLLKYQvsKSGPSAAPLYlSATWQCG 137

mu-homology domain (MHD) of F-BAR domain-containing Fer/Cip4 homology domain-only protein 2 (FCH domain only 2 or FCHo2) and similar proteins; This family corresponds to the MHD found in the ubiquitously expressed mammalian membrane-sculpting FCHo2 and similar proteins. FCHo2 represents a key initial protein that ultimately controls cellular nutrient uptake, receptor regulation, and synaptic vesicle retrieval. It is required for plasma membrane clathrin-coated vesicle (CCV) budding and marks sites of CCV formation. It binds specifically to the plasma membrane and recruits the scaffold proteins eps15 and intersectin, which subsequently engages the adaptor complex AP2 and clathrin, leading to coated vesicle formation. FCHo2 contains an N-terminal EFC/F-BAR domain, a proline-rich domain (PRD) in the middle region, and a C-terminal MHD. The crescent-shaped EFC/F-BAR domain can form an antiparallel dimer structure that binds PtdIns(4,5)P2-enriched membranes and can polymerize into rings to generate membrane tubules. The MHD is structurally related to the cargo-binding mu2 subunit of adaptor complex 2 (AP-2) and is responsible for the binding of eps15 and intersectin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871 485 PIATAFTEYVHAYFRGHSPS-CLARVTGELTMTFPAGIVRVFSGTPPPPVLSFRLVHTTAIEHFQPNADLLFSDPSQSDP 563
Cdd:cd09267     1 PVAVALTESVNAYFKGADPTkCIVKITGDMTVSFPSGIIKVFTSNPSPAVLCFRLKNTSRLEQILPNAQLLYSDPSQSDS 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1858900871 564 ETKDFWLNMAALTEALQRQAEQNPTASYYNVVLLRYQ 600
Cdd:cd09267    81 NTKDFWMNMQAVTVYLKKSSEQNPAASYYNVDILKYQ 117

Muniscin C-terminal mu homology domain; The muniscins are a family of endocytic adaptors that is conserved from yeast to humans.This C-terminal domain is structurally similar to mu homology domains, and is the region of the muniscin proteins involved in the interactions with the endocytic adaptor-scaffold proteins Ede1-eps15. This interaction influences muniscin localization. The muniscins provide a combined adaptor-membrane-tubulation activity that is important for regulating endocytosis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871 484 LPIATAFTEYVHAYFRGHSPSClARVTGELTMTFPAGIVRVFsgtPPPPVLSFRLVHTTAIEHFQPNADLLFsDPSQSDP 563
Cdd:pfam10291   1 PGLNASIAETVNAWFKDGDVTK-SKVTGEVALSYPAGIAASF---TPPAVLNFRLNNFSRLEKVAPNPAFVT-DESQSDG 75

                          90       100
                  ....*....|....*....|
gi 1858900871 564 EtkdFWLNMAALTEALQRQA 583
Cdd:pfam10291  76 E---FKVNPQFLASRTPLGA 92

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of Proline-Serine-Threonine Phosphatase-Interacting Proteins; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. Vetebrates contain two Proline-Serine-Threonine Phosphatase-Interacting Proteins (PSTPIPs), PSTPIP1 and PSTPIP2. PSTPIPs are mainly expressed in hematopoietic cells and are involved in the regulation of cell adhesion and motility. Mutations in PSTPIPs have been shown to cause autoinflammatory disorders. PSTPIP1 contains an N-terminal F-BAR domain, PEST motifs, and a C-terminal SH3 domain, while PSTPIP2 contains only the N-terminal F-BAR domain. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871   3 KLSKLASNGTPMGTFAPLWEVFRVSSDKLALCHLELTRKLQDLIKDVLRYGEEQLKTHKKCKEEVvstlDAVQVLSGVS- 81
Cdd:cd07647    44 KLSKSAGPGDEIGTLKSSWDSLRKETENVANAHIQLAQSLREEAEKLEEFREKQKEERKKTEDIM----KRSQKNKKELy 119

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871  82 QLLPKSRENYLNRCMD----QERLRRES--TSQKEMDKAETKTKKAAES-------LRRSVEKYNSARADFEQKMLDSAL 148
Cdd:cd07647   120 KKTMKAKKSYEQKCREkdkaEQAYEKSSsgAQPKEAEKLKKKAAQCKTSaeeadsaYKSSIGCLEDARVEWESEHATACQ 199

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|
gi 1858900871 149 RFQAMEETHLRHMKALLGSYAHSVEDTHVQIGQVHEEFKQ 188
Cdd:cd07647   200 VFQNMEEERIKFLRNALWVHCNLGSMQCVKLDEMYEDVRK 239

Mu-homology domain (MHD) of muniscins adaptor proteins (AP) and similar proteins; This family corresponds to the MHD found in muniscins, a novel family of endocytic adaptor proteins. The term, muniscins, has been assigned to name the MHD of proteins with both EFC/F-BAR domain and MHD. These two domains are responsible for the membrane-tubulation activity associated with transmembrane cargo proteins. Members in this family include an endocytic adaptor Syp1, the mammalian FCH domain only proteins (FCHo1/2), SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1), and related uncharacterized proteins. Syp1 is a poorly characterized yeast protein with multiple biological functions. Syp1 contains an N-terminal EFC/F-BAR domain that induces membrane tabulation, a proline-rich domain (PRD) in the middle region, and a C-terminal MHD that can directly binds to the endocytic adaptor/scaffold protein Ede1 or a transmembrane stress sensor cargo protein Mid2. Thus, Syp1 represents a novel type of endocytic adaptor protein that participates in endocytosis, promotes vesicle tabulation, and contributes to cell polarity and stress response. Syp1 shares the same domain architecture with its two ubiquitously expressed mammalian counterparts, the membrane-sculpting F-BAR domain-containing Fer/Cip4 homology domain-only proteins 1 and 2 (FCHo1/2). FCHo1/2 represent key initial proteins ultimately controlling cellular nutrient uptake, receptor regulation, and synaptic vesicle retrieval. They are required for plasma membrane clathrin-coated vesicle (CCV) budding and marked sites of CCV formation. They bind specifically to the plasma membrane and recruit the scaffold proteins eps15 and intersectin, which subsequently engage the adaptor complex AP2 and clathrin, leading to coated vesicle formation. Another mammalian neuronal-specific protein, neuronal-specific transcript Scr homology 3 (SH3)-domain growth factor receptor-bound 2 (GRB2)-like (endophilin) interacting protein 1 [SGIP1] does not contain EFC/F-BAR domain, but does have a PRD and a C-terminal MHD and has been classified into this family as well. SGIP1 is an endophilin-interacting protein that plays an obligatory role in the regulation of energy homeostasis. It is also involved in clathrin-mediated endocytosis by interacting with phospholipids and eps15.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871 485 PIATAFTEYVHAYFRGHSPSCLArVTGELTMTFPAGIVrvfsgTPPPPVLSFRLVHTTAIEHFQPNADLLFSDPSQSDPe 564
Cdd:cd09257     1 GVKAALTEELNAEFKGSSLQSVG-VEGEVQLAVPSSDA-----KPKPAPFNLRLNDASSLEKAAPNVAFLNSVPSGSSP- 73

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1858900871 565 tKDFWLNMAALtealqrqaeqnpTASYYNVVLLRYQ 600
Cdd:cd09257    74 -GEFLVNTKAI------------RASEVGSPILKYS 96

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 2; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. Proline-Serine-Threonine Phosphatase-Interacting Protein 2 (PSTPIP2), also known as Macrophage Actin-associated tYrosine Phosphorylated protein (MAYP), is mostly expressed in hematopoietic cells but is also expressed in the brain. It is involved in regulating cell adhesion and motility. Mutations in the gene encoding murine PSTPIP2 can cause autoinflammatory disorders such as chronic multifocal osteomyelitis and macrophage autoinflammatory disease. PSTPIP2 contains an N-terminal F-BAR domain and lacks the PEST motifs and SH3 domain that are found in PSTPIP1. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871   4 LSKLASNG-TPMGTFAPLWEVFRVSSDKLALCHLELTRKLQDLIKDVLRYGEEQlKTHKKCKEEVVSTLDAVQVLSGVSQ 82
Cdd:cd07672    45 LSKKKPCGqTEINTLKRSLDVFKQQIDNVGQSHIQLAQTLRDEAKKMEDFRERQ-KLARKKIELIMDAIHKQRAMQFKKT 123

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871  83 LlpKSRENYLNRCMDQERL-----RRESTS-QKEMDKAETK---TKKAAESLRRS----VEKYNSARADFEQKMLDSALR 149
Cdd:cd07672   124 M--ESKKNYEQKCRDKDEAeqavnRNANLVnVKQQEKLFAKlaqSKQNAEDADRLymqnISVLDKIREDWQKEHVKACEF 201

                         170       180       190
                  ....*....|....*....|....*....|....*....
gi 1858900871 150 FQAMEETHLRHMKALLGSYAHSVEDTHVQIGQVHEEFKQ 188
Cdd:cd07672   202 FEKQECERINFFRNAVWTHVNQLSQQCVTSDEMYEEVRK 240

The Bin/Amphiphysin/Rvs (BAR) domain, a dimerization module that binds membranes and detects membrane curvature; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions including organelle biogenesis, membrane trafficking or remodeling, and cell division and migration. Mutations in BAR containing proteins have been linked to diseases and their inactivation in cells leads to altered membrane dynamics. A BAR domain with an additional N-terminal amphipathic helix (an N-BAR) can drive membrane curvature. These N-BAR domains are found in amphiphysins and endophilins, among others. BAR domains are also frequently found alongside domains that determine lipid specificity, such as the Pleckstrin Homology (PH) and Phox Homology (PX) domains which are present in beta centaurins (ACAPs and ASAPs) and sorting nexins, respectively. A FES-CIP4 Homology (FCH) domain together with a coiled coil region is called the F-BAR domain and is present in Pombe/Cdc15 homology (PCH) family proteins, which include Fes/Fes tyrosine kinases, PACSIN or syndapin, CIP4-like proteins, and srGAPs, among others. The Inverse (I)-BAR or IRSp53/MIM homology Domain (IMD) is found in multi-domain proteins, such as IRSp53 and MIM, that act as scaffolding proteins and transducers of a variety of signaling pathways that link membrane dynamics and the underlying actin cytoskeleton. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The I-BAR domain induces membrane protrusions in the opposite direction compared to classical BAR and F-BAR domains, which produce membrane invaginations. BAR domains that also serve as protein interaction domains include those of arfaptin and OPHN1-like proteins, among others, which bind to Rac and Rho GAP domains, respectively.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871  30 KLALCHLELTRKLQDLIKDVLRYGEEQLKTHKKCKEEVVSTLDaVQVLSGVSQLLpksrENYLN---RCMDQERLRREST 106
Cdd:cd07307    32 KLSEALQELGKELPDLSNTDLGEALEKFGKIQKELEEFRDQLE-QKLENKVIEPL----KEYLKkdlKEIKKRRKKLDKA 106

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1858900871 107 SQkEMDKAETKTKKAAESLRRSV------EKYNSARADFEQKMLDSALRFQAMEETHLRHMKALLGSYAHSVEDTHVQIG 180
Cdd:cd07307   107 RL-DYDAAREKLKKLRKKKKDSSklaeaeEELQEAKEKYEELREELIEDLNKLEEKRKELFLSLLLSFIEAQSEFFKEVL 185

                  ....*....
gi 1858900871 181 QVHEEFKQN 189
Cdd:cd07307   186 KILEQLLPY 194