ID STAR_HUMAN Reviewed; 285 AA. AC P49675; Q16396; DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot. DT 19-JUL-2005, sequence version 2. DT 24-JAN-2024, entry version 213. DE RecName: Full=Steroidogenic acute regulatory protein, mitochondrial; DE Short=StAR; DE AltName: Full=START domain-containing protein 1; DE Short=StARD1; DE Flags: Precursor; GN Name=STAR; Synonyms=STARD1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], VARIANT ASP-203, FUNCTION, AND CATALYTIC RP ACTIVITY. RC TISSUE=Adrenal cortex; RX PubMed=7761400; DOI=10.1073/pnas.92.11.4778; RA Sugawara T., Holt J.A., Driscoll D., Strauss J.F. III, Lin D., Miller W.L., RA Patterson D., Clancy K.P., Hart I.M., Clark B.J., Stocco D.M.; RT "Human steroidogenic acute regulatory protein: functional activity in COS-1 RT cells, tissue-specific expression, and mapping of the structural gene to RT 8p11.2 and a pseudogene to chromosome 13."; RL Proc. Natl. Acad. Sci. U.S.A. 92:4778-4782(1995). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ASP-203. RC TISSUE=Placenta; RX PubMed=7547998; DOI=10.1021/bi00039a004; RA Sugawara T., Lin D., Holt J.A., Martin K.O., Javitt N.B., Miller W.L., RA Strauss J.F. III; RT "Structure of the human steroidogenic acute regulatory protein (StAR) gene: RT StAR stimulates mitochondrial cholesterol 27-hydroxylase activity."; RL Biochemistry 34:12506-12512(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=7548191; DOI=10.1016/0005-2760(95)00140-8; RA Gradi A., Tang-Wai R., McBride H.M., Chu L.L., Shore G.C., Pelletier J.; RT "The human steroidogenic acute regulatory (StAR) gene is expressed in the RT urogenital system and encodes a mitochondrial polypeptide."; RL Biochim. Biophys. Acta 1258:228-233(1995). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RA Yu W., Sarginson J., Gibbs R.A.; RL Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP PHOSPHORYLATION AT SER-57 AND SER-195. RX PubMed=10548884; RA Strauss J.F. III, Kallen C.B., Christenson L.K., Watari H., Devoto L., RA Arakane F., Kiriakidou M., Sugawara T.; RT "The steroidogenic acute regulatory protein (StAR): a window into the RT complexities of intracellular cholesterol trafficking."; RL Recent Prog. Horm. Res. 54:369-394(1999). RN [7] RP X-RAY CRYSTALLOGRAPHY (3.40 ANGSTROMS) OF 66-284. RX PubMed=21738568; DOI=10.1371/journal.pone.0019521; RA Thorsell A.G., Lee W.H., Persson C., Siponen M.I., Nilsson M., Busam R.D., RA Kotenyova T., Schuler H., Lehtio L.; RT "Comparative structural analysis of lipid binding START domains."; RL PLoS ONE 6:E19521-E19521(2011). RN [8] RP CATALYTIC ACTIVITY, INVOLVEMENT IN AH1, AND FUNCTION. RX PubMed=7892608; DOI=10.1126/science.7892608; RA Lin D., Sugawara T., Strauss J.F. III, Clark B.J., Stocco D.M., Saenger P., RA Rogol A., Miller W.L.; RT "Role of steroidogenic acute regulatory protein in adrenal and gonadal RT steroidogenesis."; RL Science 267:1828-1831(1995). RN [9] RP VARIANTS AH1 GLY-169; LYS-169; LEU-182; VAL-218; ARG-272 DEL AND PRO-275, RP CHARACTERIZATION OF VARIANTS AH1 GLY-169; LYS-169; LEU-182; VAL-218; RP ARG-272 DEL AND PRO-275, AND CATALYTIC ACTIVITY. RX PubMed=8948562; DOI=10.1056/nejm199612193352503; RA Bose H.S., Sugawara T., Strauss J.F. III, Miller W.L.; RT "The pathophysiology and genetics of congenital lipoid adrenal RT hyperplasia."; RL N. Engl. J. Med. 335:1870-1878(1996). RN [10] RP VARIANTS AH1 VAL-218 AND THR-225. RX PubMed=9097960; DOI=10.1093/hmg/6.4.571; RA Nakae J., Tajima T., Sugawara T., Arakane F., Hanaki K., Hotsubo T., RA Igarashi N., Igarashi Y., Ishii T., Koda N., Kondo T., Kohno H., RA Nakagawa Y., Tachibana K., Takeshima Y., Tsubouchi K., Strauss J.F. III, RA Fujieda K.; RT "Analysis of the steroidogenic acute regulatory protein (StAR) gene in RT Japanese patients with congenital lipoid adrenal hyperplasia."; RL Hum. Mol. Genet. 6:571-576(1997). RN [11] RP VARIANT ASP-203. RX PubMed=9452116; DOI=10.1002/humu.1380110195; RA Katsumata N., Tanae A., Shinagawa T., Nagashima-Miyokawa A., Shimizu M., RA Yasunaga T., Tanaka T., Hibi I.; RT "A novel frameshift mutation 840delA and a novel polymorphism D203A in the RT steroidogenic acute regulatory protein gene in a Japanese patient with RT congenital lipoid adrenal hyperplasia."; RL Hum. Mutat. Suppl. 1:S304-S307(1998). RN [12] RP VARIANTS AH1 THR-217 AND VAL-218. RX PubMed=10566637; DOI=10.1210/jcem.84.11.6118; RA Katsumata N., Kawada Y., Yamamoto Y., Noda M., Nimura A., Horikawa R., RA Tanaka T.; RT "A novel compound heterozygous mutation in the steroidogenic acute RT regulatory protein gene in a patient with congenital lipoid adrenal RT hyperplasia."; RL J. Clin. Endocrinol. Metab. 84:3983-3987(1999). CC -!- FUNCTION: Plays a key role in steroid hormone synthesis by enhancing CC the metabolism of cholesterol into pregnenolone. Mediates the transfer CC of cholesterol from the outer mitochondrial membrane to the inner CC mitochondrial membrane where it is cleaved to pregnenolone. CC {ECO:0000269|PubMed:7761400, ECO:0000269|PubMed:7892608, CC ECO:0000269|PubMed:8948562}. CC -!- CATALYTIC ACTIVITY: CC Reaction=cholesterol(in) = cholesterol(out); Xref=Rhea:RHEA:39747, CC ChEBI:CHEBI:16113; Evidence={ECO:0000269|PubMed:7761400, CC ECO:0000269|PubMed:7892608}; CC -!- PATHWAY: Steroid metabolism; cholesterol metabolism. CC {ECO:0000305|PubMed:7761400}. CC -!- SUBUNIT: May interact with TSPO. {ECO:0000250|UniProtKB:P79245}. CC -!- INTERACTION: CC P49675; Q6RW13-2: AGTRAP; NbExp=3; IntAct=EBI-722932, EBI-11522760; CC P49675; Q8IZR5-2: CMTM4; NbExp=3; IntAct=EBI-722932, EBI-17278014; CC P49675; Q6ZPD8: DGAT2L6; NbExp=3; IntAct=EBI-722932, EBI-12831978; CC P49675; P42858: HTT; NbExp=3; IntAct=EBI-722932, EBI-466029; CC P49675; G5E962: MAGEA11; NbExp=3; IntAct=EBI-722932, EBI-11525615; CC P49675; P43364: MAGEA11; NbExp=6; IntAct=EBI-722932, EBI-739552; CC P49675; P43364-2: MAGEA11; NbExp=3; IntAct=EBI-722932, EBI-10178634; CC P49675; Q15276: RABEP1; NbExp=3; IntAct=EBI-722932, EBI-447043; CC P49675; O60906: SMPD2; NbExp=3; IntAct=EBI-722932, EBI-12828299; CC P49675; Q9UNK0: STX8; NbExp=3; IntAct=EBI-722932, EBI-727240; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:P51557}. CC -!- TISSUE SPECIFICITY: Expressed in gonads, adrenal cortex and kidney. CC -!- DISEASE: Adrenal hyperplasia 1 (AH1) [MIM:201710]: The most severe form CC of adrenal hyperplasia. It is a condition characterized by onset of CC profound adrenocortical insufficiency shortly after birth, CC hyperpigmentation reflecting increased production of pro- CC opiomelanocortin, elevated plasma renin activity as a consequence of CC reduced aldosterone synthesis, and male pseudohermaphroditism resulting CC from deficient fetal testicular testosterone synthesis. Affected CC individuals are phenotypic females irrespective of gonadal sex, and CC frequently die in infancy if mineralocorticoid and glucocorticoid CC replacement are not instituted. {ECO:0000269|PubMed:10566637, CC ECO:0000269|PubMed:7892608, ECO:0000269|PubMed:8948562, CC ECO:0000269|PubMed:9097960}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Steroidogenic acute regulatory CC protein entry; CC URL="https://en.wikipedia.org/wiki/Steroidogenic_acute_regulatory_protein"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U17280; AAC50141.1; -; mRNA. DR EMBL; U29105; AAC50234.1; -; Genomic_DNA. DR EMBL; U29099; AAC50234.1; JOINED; Genomic_DNA. DR EMBL; U29100; AAC50234.1; JOINED; Genomic_DNA. DR EMBL; U29101; AAC50234.1; JOINED; Genomic_DNA. DR EMBL; U29102; AAC50234.1; JOINED; Genomic_DNA. DR EMBL; U29103; AAC50234.1; JOINED; Genomic_DNA. DR EMBL; U29104; AAC50234.1; JOINED; Genomic_DNA. DR EMBL; S79669; AAB35726.1; -; mRNA. DR EMBL; AF035277; AAB88174.1; -; mRNA. DR EMBL; BC010550; AAH10550.1; -; mRNA. DR CCDS; CCDS6102.1; -. DR PIR; I38248; I38248. DR RefSeq; NP_000340.2; NM_000349.2. DR PDB; 3P0L; X-ray; 3.40 A; A/B/C/D=66-284. DR PDB; 5OMA; X-ray; 3.90 A; A/B/C/D=54-62. DR PDB; 6T5F; X-ray; 2.63 A; E/F/G/H=192-200. DR PDB; 6T5H; X-ray; 2.04 A; A/B=54-62. DR PDBsum; 3P0L; -. DR PDBsum; 5OMA; -. DR PDBsum; 6T5F; -. DR PDBsum; 6T5H; -. DR AlphaFoldDB; P49675; -. DR SMR; P49675; -. DR BioGRID; 112647; 11. DR IntAct; P49675; 11. DR STRING; 9606.ENSP00000276449; -. DR SwissLipids; SLP:000000714; -. DR SwissLipids; SLP:000000716; -. DR iPTMnet; P49675; -. DR PhosphoSitePlus; P49675; -. DR BioMuta; STAR; -. DR DMDM; 71152974; -. DR EPD; P49675; -. DR MassIVE; P49675; -. DR PaxDb; 9606-ENSP00000276449; -. DR PeptideAtlas; P49675; -. DR ProteomicsDB; 56046; -. DR Pumba; P49675; -. DR Antibodypedia; 23510; 443 antibodies from 35 providers. DR DNASU; 6770; -. DR Ensembl; ENST00000276449.9; ENSP00000276449.3; ENSG00000147465.12. DR GeneID; 6770; -. DR KEGG; hsa:6770; -. DR MANE-Select; ENST00000276449.9; ENSP00000276449.3; NM_000349.3; NP_000340.2. DR AGR; HGNC:11359; -. DR CTD; 6770; -. DR DisGeNET; 6770; -. DR GeneCards; STAR; -. DR HGNC; HGNC:11359; STAR. DR HPA; ENSG00000147465; Tissue enriched (adrenal). DR MalaCards; STAR; -. DR MIM; 201710; phenotype. DR MIM; 600617; gene. DR neXtProt; NX_P49675; -. DR OpenTargets; ENSG00000147465; -. DR Orphanet; 325524; Classic congenital lipoid adrenal hyperplasia due to STAR deficency. DR Orphanet; 361; Familial glucocorticoid deficiency. DR Orphanet; 325529; Non-classic congenital lipoid adrenal hyperplasia due to STAR deficency. DR PharmGKB; PA36181; -. DR VEuPathDB; HostDB:ENSG00000147465; -. DR eggNOG; KOG3845; Eukaryota. DR GeneTree; ENSGT00940000155477; -. DR HOGENOM; CLU_093200_1_0_1; -. DR InParanoid; P49675; -. DR OMA; PSAWINQ; -. DR OrthoDB; 5346886at2759; -. DR PhylomeDB; P49675; -. DR TreeFam; TF313869; -. DR PathwayCommons; P49675; -. DR Reactome; R-HSA-196108; Pregnenolone biosynthesis. DR SignaLink; P49675; -. DR SIGNOR; P49675; -. DR UniPathway; UPA00296; -. DR BioGRID-ORCS; 6770; 9 hits in 1156 CRISPR screens. DR ChiTaRS; STAR; human. DR EvolutionaryTrace; P49675; -. DR GenomeRNAi; 6770; -. DR Pharos; P49675; Tbio. DR PRO; PR:P49675; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; P49675; Protein. DR Bgee; ENSG00000147465; Expressed in right adrenal gland and 115 other cell types or tissues. DR ExpressionAtlas; P49675; baseline and differential. DR GO; GO:0005758; C:mitochondrial intermembrane space; TAS:Reactome. DR GO; GO:0015485; F:cholesterol binding; IDA:BHF-UCL. DR GO; GO:0120020; F:cholesterol transfer activity; IEA:InterPro. DR GO; GO:0044255; P:cellular lipid metabolic process; IEA:Ensembl. DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-UniPathway. DR GO; GO:0008211; P:glucocorticoid metabolic process; IEA:Ensembl. DR GO; GO:0032367; P:intracellular cholesterol transport; IBA:GO_Central. DR GO; GO:0070859; P:positive regulation of bile acid biosynthetic process; IDA:BHF-UCL. DR GO; GO:0050810; P:regulation of steroid biosynthetic process; IBA:GO_Central. DR GO; GO:0006694; P:steroid biosynthetic process; IBA:GO_Central. DR CDD; cd08905; START_STARD1-like; 1. DR Gene3D; 3.30.530.20; -; 1. DR InterPro; IPR029866; StAR. DR InterPro; IPR000799; StAR-like. DR InterPro; IPR023393; START-like_dom_sf. DR InterPro; IPR002913; START_lipid-bd_dom. DR PANTHER; PTHR46489; STEROIDOGENIC ACUTE REGULATORY PROTEIN, MITOCHONDRIAL; 1. DR PANTHER; PTHR46489:SF1; STEROIDOGENIC ACUTE REGULATORY PROTEIN, MITOCHONDRIAL; 1. DR Pfam; PF01852; START; 1. DR PRINTS; PR00978; STARPROTEIN. DR SMART; SM00234; START; 1. DR SUPFAM; SSF55961; Bet v1-like; 1. DR PROSITE; PS50848; START; 1. DR Genevisible; P49675; HS. PE 1: Evidence at protein level; KW 3D-structure; Congenital adrenal hyperplasia; Disease variant; KW Lipid transport; Lipid-binding; Mitochondrion; Phosphoprotein; KW Reference proteome; Steroidogenesis; Transit peptide; Transport. FT TRANSIT 1..63 FT /note="Mitochondrion" FT /evidence="ECO:0000250" FT CHAIN 64..285 FT /note="Steroidogenic acute regulatory protein, FT mitochondrial" FT /id="PRO_0000033316" FT DOMAIN 67..280 FT /note="START" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00197" FT MOD_RES 57 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:10548884" FT MOD_RES 195 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:10548884" FT VARIANT 121 FT /note="R -> W (in dbSNP:rs34908868)" FT /id="VAR_034520" FT VARIANT 169 FT /note="E -> G (in AH1; partial loss of activity; FT dbSNP:rs1254559989)" FT /evidence="ECO:0000269|PubMed:8948562" FT /id="VAR_014236" FT VARIANT 169 FT /note="E -> K (in AH1; partial loss of activity; FT dbSNP:rs747169620)" FT /evidence="ECO:0000269|PubMed:8948562" FT /id="VAR_014237" FT VARIANT 182 FT /note="R -> L (in AH1; partial loss of activity; FT dbSNP:rs104894086)" FT /evidence="ECO:0000269|PubMed:8948562" FT /id="VAR_005627" FT VARIANT 203 FT /note="A -> D (in dbSNP:rs1042854)" FT /evidence="ECO:0000269|PubMed:7547998, FT ECO:0000269|PubMed:7761400, ECO:0000269|PubMed:9452116" FT /id="VAR_005628" FT VARIANT 217 FT /note="R -> T (in AH1; dbSNP:rs137852689)" FT /evidence="ECO:0000269|PubMed:10566637" FT /id="VAR_014238" FT VARIANT 218 FT /note="A -> V (in AH1; partial loss of activity; FT dbSNP:rs137852690)" FT /evidence="ECO:0000269|PubMed:10566637, FT ECO:0000269|PubMed:8948562, ECO:0000269|PubMed:9097960" FT /id="VAR_014239" FT VARIANT 225 FT /note="M -> T (in AH1; dbSNP:rs1446362214)" FT /evidence="ECO:0000269|PubMed:9097960" FT /id="VAR_014240" FT VARIANT 272 FT /note="Missing (in AH1; partial loss of activity)" FT /evidence="ECO:0000269|PubMed:8948562" FT /id="VAR_014241" FT VARIANT 275 FT /note="L -> P (in AH1; partial loss of activity; FT dbSNP:rs762245736)" FT /evidence="ECO:0000269|PubMed:8948562" FT /id="VAR_014242" FT HELIX 70..91 FT /evidence="ECO:0007829|PDB:3P0L" FT STRAND 97..101 FT /evidence="ECO:0007829|PDB:3P0L" FT STRAND 107..112 FT /evidence="ECO:0007829|PDB:3P0L" FT STRAND 114..116 FT /evidence="ECO:0007829|PDB:3P0L" FT STRAND 118..128 FT /evidence="ECO:0007829|PDB:3P0L" FT HELIX 130..137 FT /evidence="ECO:0007829|PDB:3P0L" FT TURN 138..140 FT /evidence="ECO:0007829|PDB:3P0L" FT HELIX 141..143 FT /evidence="ECO:0007829|PDB:3P0L" FT STRAND 152..159 FT /evidence="ECO:0007829|PDB:3P0L" FT STRAND 161..171 FT /evidence="ECO:0007829|PDB:3P0L" FT STRAND 182..192 FT /evidence="ECO:0007829|PDB:3P0L" FT STRAND 197..199 FT /evidence="ECO:0007829|PDB:3P0L" FT STRAND 215..217 FT /evidence="ECO:0007829|PDB:3P0L" FT STRAND 224..230 FT /evidence="ECO:0007829|PDB:3P0L" FT STRAND 233..243 FT /evidence="ECO:0007829|PDB:3P0L" FT HELIX 253..274 FT /evidence="ECO:0007829|PDB:3P0L" SQ SEQUENCE 285 AA; 31914 MW; 2683086C20DE88AB CRC64; MLLATFKLCA GSSYRHMRNM KGLRQQAVMA ISQELNRRAL GGPTPSTWIN QVRRRSSLLG SRLEETLYSD QELAYLQQGE EAMQKALGIL SNQEGWKKES QQDNGDKVMS KVVPDVGKVF RLEVVVDQPM ERLYEELVER MEAMGEWNPN VKEIKVLQKI GKDTFITHEL AAEAAGNLVG PRDFVSVRCA KRRGSTCVLA GMATDFGNMP EQKGVIRAEH GPTCMVLHPL AGSPSKTKLT WLLSIDLKGW LPKSIINQVL SQTQVDFANH LRKRLESHPA SEARC //