in StAR and phosphatidylcholine transfer protein; putative lipid-binding domain in StAR and phosphatidylcholine transfer protein

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035   154 RRPITGTHLYQYRVFGTYTDVTPRQFFNVQLDTEYRKKWDALVIKLEVIERdVVSGSEVLHWVTHFPY-PMYSRDYVYVR 232
Cdd:smart00234  35 IFSPGRKPGEAFRLVGVVPMVCADLVEELMDDLEYRPEWDKNVAKAETLEV-IDNGTVIYHYVSKFAAgPVSPRDFVFVR 113

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035   233 RYSVDqENNMMVLVSRAVEHPSVPESPEFVRVRSYESQMVIRPhksfDENG---FDYLltYSDNPQTVFPRYCVSWMVSS 309
Cdd:smart00234 114 YWRED-EDGSYAVVDVSVTHPTSPPESGYVRAENLPSGLLIEP----LGNGpskVTWV--SHADLKGWLPHWLVRSLIKS 186

                          170
                   ....*....|....*.
gi 151301035   310 GMPDFLeKLHMATLKA 325
Cdd:smart00234 187 GLAEFA-KTLVATLQK 201

Lipid-binding START domain of mammalian STARD2, -7, and related proteins; This subfamily includes the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains of STARD2 (also known as phosphatidylcholine transfer protein/PC-TP), and STARD7 (also known as gestational trophoblastic tumor 1/GTT1). The START domain family belongs to the SRPBCC (START/RHO_alpha_C/PITP/Bet_v1/CoxG/CalC) domain superfamily of proteins that bind hydrophobic ligands. SRPBCC domains have a deep hydrophobic ligand-binding pocket. STARD2 is a cytosolic phosphatidycholine (PtdCho) transfer protein, which traffics PtdCho, the most common class of phospholipids in eukaryotes, between membranes. It represents a minimal START domain structure. STARD2 plays roles in hepatic cholesterol metabolism, in the development of atherosclerosis, and may also have a mitochondrial function. The gene encoding STARD7 is overexpressed in choriocarcinoma. STARD7 appears to be involved in the intracellular trafficking of PtdCho to mitochondria. STARD7 was shown to be surface active and to interact differentially with phospholipid monolayers. It showed a preference for phosphatidylserine, cholesterol, and phosphatidylglycerol.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035 119 HHPPEPKAQTEGNEDSEGKE-QRWEMVMDKKH----FKLWRRPITGTHLYQYRVFGTYTDVTPRQFFNVQLDTEYRKKWD 193
Cdd:cd08870    1 GHVSEEDLRDLVQELQEGAEgQAWQQVMDKSTpdmsYQAWRRKPKGTGLYEYLVRGVFEDCTPELLRDFYWDDEYRKKWD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035 194 ALVIKLEVIERDVVSGSEVLHWVTHFPYPMYSRDYVYVRRYSVDQeNNMMVLVSRAVEHPSVPESpEFVRVRSYESQMVI 273
Cdd:cd08870   81 ETVIEHETLEEDEKSGTEIVRWVKKFPFPLSDREYVIARRLWESD-DRSYVCVTKGVPYPSVPRS-GRKRVDDYESSLVI 158

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|..
gi 151301035 274 RPHKsFDENGFDYLLTYSDNPQTVFPRYCVSWMVSSGMPDFLEKLHMATLKA 325
Cdd:cd08870  159 RAVK-GDGQGSACEVTYFHNPDGGIPRELAKLAVKRGMPGFLKKLENALRKY 209

Lipid-binding START domain of mammalian STARD1-STARD15 and related proteins; This family includes the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains of mammalian STARD1-STARD15, and related domains, such as the START domain of the Arabidopsis homeobox protein GLABRA 2. The mammalian STARDs are grouped into 8 subfamilies. This family belongs to the SRPBCC (START/RHO_alpha_C/PITP/Bet_v1/CoxG/CalC) domain superfamily of proteins that bind hydrophobic ligands. SRPBCC domains have a deep hydrophobic ligand-binding pocket. For some members of this family, specific lipids that bind in this pocket are known; these include cholesterol (STARD1/STARD3/ STARD4/STARD5), 25-hydroxycholesterol (STARD5), phosphatidylcholine (STARD2/ STARD7/STARD10), phosphatidylethanolamine (STARD10) and ceramides (STARD11). The START domain is found either alone or in association with other domains. Mammalian STARDs participate in the control of various cellular processes including lipid trafficking between intracellular compartments, lipid metabolism, and modulation of signaling events. Mutation or altered expression of STARDs is linked to diseases such as cancer, genetic disorders, and autoimmune disease. The Arabidopsis homeobox protein GLABRA 2 suppresses root hair formation in hairless epidermal root cells.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035 131 NEDSEGKEQRWEMVMDKKHFKLWRRPITGTHLYQYRVFGTyTDVTPRQFFNVQLDTEYRKKWDALVIKLEVIErDVVSGS 210
Cdd:cd00177    7 LLELLEEPEGWKLVKEKDGVKIYTKPYEDSGLKLLKAEGV-IPASPEQVFELLMDIDLRKKWDKNFEEFEVIE-EIDEHT 84

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 151301035 211 EVLHWVTHFPYPMYSRDYVYVRRYSVDQEnNMMVLVSRAVEHPSVPESPEFVRVRSYESQMVIRPH 276
Cdd:cd00177   85 DIIYYKTKPPWPVSPRDFVYLRRRRKLDD-GTYVIVSKSVDHDSHPKEKGYVRAEIKLSGWIIEPL 149

Lipid-binding START domain of mammalian STARD10 and related proteins; This subfamily includes the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains of mammalian STARD10 (also known as CGI-52, PTCP-like, and SDCCAG28). The START domain family belongs to the SRPBCC (START/RHO_alpha_C/PITP/Bet_v1/CoxG/CalC) domain superfamily of proteins that bind hydrophobic ligands. SRPBCC domains have a deep hydrophobic ligand-binding pocket. STARD10 binds phophatidylcholine and phosphatidylethanolamine. This protein is widely expressed and is synthesized constitutively in many organs. It may function in the liver in the export of phospholipids into bile. It is concentrated in the sperm flagellum, and may play a role in energy metabolism. In the mammary gland it may participate in the enrichment of lipids in milk, and be a potential marker of differentiation. Its expression is induced in this gland during gestation and lactation. It is overexpressed in mammary tumors from Neu/ErbB2 transgenic mice, in several breast carcinoma cell lines, and in 35% of primary human breast cancers, and may cooperate with c-erbB receptor signaling in breast oncogenesis. It is a potential marker of disease outcome in breast cancer; loss of STARD10 expression in breast cancer strongly predicts an aggressive disease course. The lipid transfer activity of STRAD10 is downregulated by phosphorylation of its Ser284 by CK2 (casein kinase 2).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035 132 EDSEGkeqrWEMVMDKKHFKLWRRPITGTHLYQYRVFGTYTDVTPRQFFNVQLDTEYRKKWDALVIKLEVIERdVVSGSE 211
Cdd:cd08871   20 DSTDG----WKLKYNKNNVKVWTKNPENSSIKMIKVSAIFPDVPAETLYDVLHDPEYRKTWDSNMIESFDICQ-LNPNND 94

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035 212 VLHWVTHFPYPMYSRDYVYVRRY-SVDQEnnmMVLVSRAVEHPSVPESPEFVRVRSYESQMVIRPhksFDENG--FDYlL 288
Cdd:cd08871   95 IGYYSAKCPKPLKNRDFVNLRSWlEFGGE---YIIFNHSVKHKKYPPRKGFVRAISLLTGYLIRP---TGPKGctLTY-V 167

                        170       180       190
                 ....*....|....*....|....*....|....*.
gi 151301035 289 TYSDnPQTVFPRYCVSWMVSSGMPDFLEKLHMATLK 324
Cdd:cd08871  168 TQND-PKGSLPKWVVNKATTKLAPKVMKKLHKAALK 202

START domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035  161 HLYQYRVFGTYTDVTPRQFFNVQLDTEYRKKWDALVIKLEVIERdVVSGSEVLHWVTHF--PYPMYSRDYVYVRRYSVDq 238
Cdd:pfam01852  41 HGEASRASGVVPMVAALLVAELLKDMEYRAQWDKDVRSAETLEV-ISSGGDLQYYVAALvaPSPLSPRDFVFLRYWRRL- 118

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035  239 ENNMMVLVSRAVEHPSVPESPEFVRVRSYESQMVIRPhksfDENG---FDYLltYSDNPQTVFPRYCVSWMVSSGMPDFL 315
Cdd:pfam01852 119 GGGVYVIVDRSVTHPQFPPSSGYVRAERLPSGYLIQP----CGNGpskVTWV--SHADLKGWLPSWLLRSLYKSGMPEGA 192

                  ....*....
gi 151301035  316 eKLHMATLK 324
Cdd:pfam01852 193 -KTWVATLQ 200

Cholesterol-binding START domain of mammalian STARD1, -3 and related proteins; This subfamily includes the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains of STARD1 (also known as StAR) and STARD3 (also known as metastatic lymph node 64/MLN64). The START domain family belongs to the SRPBCC (START/RHO_alpha_C/PITP/Bet_v1/CoxG/CalC) domain superfamily of proteins that bind hydrophobic ligands. SRPBCC domains have a deep hydrophobic ligand-binding pocket. This STARD1-like subfamily has a high affinity for cholesterol. STARD1/StAR can reduce macrophage lipid content and inflammatory status. It plays an essential role in steroidogenic tissues: transferring the steroid precursor, cholesterol, from the outer to the inner mitochondrial membrane, across the aqueous space. Mutations in the gene encoding STARD1/StAR can cause lipid congenital adrenal hyperplasia (CAH), an autosomal recessive disorder characterized by a steroid synthesis deficiency and an accumulation of cholesterol in the adrenal glands and the gonads. STARD3 may function in trafficking endosomal cholesterol to a cytosolic acceptor or membrane. In addition to having a cytoplasmic START cholesterol-binding domain, STARD3 also contains an N-terminal MENTAL cholesterol-binding and protein-protein interaction domain. The MENTAL domain contains transmembrane helices and anchors MLN64 to endosome membranes. The gene encoding STARD3 is overexpressed in about 25% of breast cancers.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035 173 DVTPRQFFN-VQLDTEYRKKWDALVIKLEVIERdVVSGSEVLHWVTHfpyP-----MYSRDYVYVRRYSVdqENNMMVLV 246
Cdd:cd08868   57 DCPAEFLYNeLVLNVESLPSWNPTVLECKIIQV-IDDNTDISYQVAA---EaggglVSPRDFVSLRHWGI--RENCYLSS 130

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035 247 SRAVEHPSVPESPEFVRVRSYESQMVIRPHKSF-DENGFDYLLtySDNPQTVFPRYCVSWMVSSGMPDFLE--KLHMATL 323
Cdd:cd08868  131 GVSVEHPAMPPTKNYVRGENGPGCWILRPLPNNpNKCNFTWLL--NTDLKGWLPQYLVDQALASVLLDFMKhlRKRIATL 208

C-terminal lipid-binding START domain of mammalian STARD8, -12, -13 and related proteins, which also have an N-terminal Rho GTPase-activating protein (RhoGAP) domain; This subfamily includes the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains of STARD8 (also known as deleted in liver cancer 3/DLC3, and Arhgap38), STARD12 (also known as DLC-1, Arhgap7, and p122-RhoGAP), and STARD13 (also known as DLC-2, Arhgap37, and SDCCAG13). The START domain family belongs to the SRPBCC (START/RHO_alpha_C/PITP/Bet_v1/CoxG/CalC) domain superfamily of proteins that bind hydrophobic ligands. SRPBCC domains have a deep hydrophobic ligand-binding pocket. Proteins belonging to this subfamily also have a RhoGAP domain. Some, including STARD12, -and -13, also have an N-terminal SAM (sterile alpha motif) domain; these have a SAM-RhoGAP-START domain organization. This subfamily is involved in cancer development. A large spectrum of cancers have dysregulated genes encoding these proteins. The precise function of the START domain in this subfamily is unclear.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035 189 RKKWDALVIKLEVIERdVVSGSEVLHWVTHFPYPMYSRDYVYVRRYSVDQENNMMVLVSRAVEHPSvPESPEFVRVRSYE 268
Cdd:cd08869   67 RHLWDDDLLQWKVVET-LDEDTEVYQYVTNSMAPHPTRDYVVLRTWRTDLPKGACVLVETSVEHTE-PVPLGGVRAVVLA 144

                 ....*..
gi 151301035 269 SQMVIRP 275
Cdd:cd08869  145 SRYLIEP 151

Ceramide-binding START domain of mammalian STARD11 and related domains; This subfamily includes the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains of mammalian STARD11 and related domains. The START domain family belongs to the SRPBCC (START/RHO_alpha_C/PITP/Bet_v1/CoxG/CalC) domain superfamily of proteins that bind hydrophobic ligands. SRPBCC domains have a deep hydrophobic ligand-binding pocket. STARD11 can mediate transfer of the natural ceramide isomers, dihydroceramide and phytoceramide, as well as ceramides having C14, C16, C18, and C20 chains. They can also transfer diacylglycerol, but with a lower efficiency. STARD11 is synthesized from two major transcripts: a larger one encoding Goodpasture antigen-binding protein (GPBP)/ceramide transporter long form (CERTL); and a smaller one encoding GPBPdelta26/CERT, which is deleted for 26 amino acids. Both splicing variants mediate ceramide transfer from the ER to the Golgi, in a non-vesicular manner. It is likely that these two carry out different functions in specific sub-cellular locations. These proteins have roles in brain homeostasis and disease processes. GPBP/CERTL exists in multiple isoforms originating from alternative translation initiation sites and post-translational modifications. Goodpasture syndrome is a human disorder caused by antibodies directed against the a3-chain of collagen type IV. GPBP/CERTL binds and phosphorylates this antigen. The human gene encoding STARD11 is referred to as COL4A3BP referring to its collagen binding function. It is unknown whether the ceramide-transfer function of GPBP/CERTL is related to this collagen interaction. The expression of GPBP/CERTL is elevated in these and other spontaneous autoimmune disorders including cutaneous lupus erythematosus, pemphigoid, and lichen planus. GPBL/CERTL contains an N-terminal pleckstrin homology domain (PH), which targets the protein to the Golgi, a middle region containing two serine-rich domains (SR1, SR2), a FFAT (two phenylalanine amino acids in an acidic tract) motif which is involved in endoplasmic reticulum targeting, and this C-terminal SMART domain. The shorter splicing variant, CERT, lacks the SR2 domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 151301035 141 WEMVMDKKHFKLWRRpitgthlyQYRVFGTYTD----------VTPRQFFNVQLDTEYRKKWDALVIKLEVIErdVVSGS 210
Cdd:cd08872   28 WQLFAEEGEMKVYRR--------EVEEDGVVLDplkathavkgVTGHEVCHYFFDPDVRMDWETTLENFHVVE--TLSQD 97

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 151301035 211 EVLHWVTHFP-YPMYSRDYVYV---RRYSVDQENN---MMVLVSRAVEHPSVPESPEFVRVR 265
Cdd:cd08872   98 TLIFHQTHKRvWPAAQRDALFVshiRKIPALEEPNahdTWIVCNFSVDHDSAPLNNKCVRAK 159

Lipid-binding START domain of mammalian STARD15 and related proteins; This subgroup includes the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains of STARD15/ACOT12 (also known as cytoplasmic acetyl-CoA hydrolase/CACH, THEAL, and MGC105114) and related domains. It belongs to the START domain family, and in turn to the SRPBCC (START/RHO_alpha_C/PITP/Bet_v1/CoxG/CalC) domain superfamily of proteins that bind hydrophobic ligands. SRPBCC domains have a deep hydrophobic ligand-binding pocket. STARD15/ACOT12 is a type II acetyl-CoA thioesterase; it catalyzes the hydrolysis of acyl-CoAs to free fatty acid and CoASH. Rat CACH hydrolyzes acetyl-CoA to acetate and CoA. In addition to having a START domain, most proteins in this subgroup have two tandem copies of the hotdog domain. Human STARD15/ACOT12 may have roles in cholesterol metabolism and in beta-oxidation.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 151301035 189 RKKWDALVIKLEVIERdvVSGSEVLHWVTHFPYPM-YSRDYVYV--RRYSVDQENNMMVLVsRAVEHPSVPESPEFVR 263
Cdd:cd08914  103 RPLWDPHFLSCEVIDW--VSEDDQIYHITCPIVNNdKPKDLVVLvsRRKPLKDGNTYVVAV-KSVILPSVPPSPQYIR 177