ID AL5AP_HUMAN Reviewed; 161 AA. AC P20292; Q5VV04; DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-1992, sequence version 2. DT 24-JAN-2024, entry version 188. DE RecName: Full=Arachidonate 5-lipoxygenase-activating protein; DE AltName: Full=FLAP; DE AltName: Full=MK-886-binding protein; GN Name=ALOX5AP; Synonyms=FLAP; 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], AND FUNCTION. RX PubMed=2300173; DOI=10.1038/343282a0; RA Dixon R.A.F., Diehl R.E., Opas E., Rands E., Vickers P.J., Evans J.F., RA Gillard J.W., Miller D.K.; RT "Requirement of a 5-lipoxygenase-activating protein for leukotriene RT synthesis."; RL Nature 343:282-284(1990). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=1673682; DOI=10.1016/s0021-9258(18)93004-8; RA Kennedy B.P., Diehl R.E., Boie Y., Adam M., Dixon R.A.F.; RT "Gene characterization and promoter analysis of the human 5-lipoxygenase- RT activating protein (FLAP)."; RL J. Biol. Chem. 266:8511-8516(1991). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG SeattleSNPs variation discovery resource; RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057823; DOI=10.1038/nature02379; RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., RA Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., RA Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L., RA Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., RA Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., RA Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., RA Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., RA Frankish A.G., Frankland J., French L., Garner P., Garnett J., RA Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., RA Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., RA Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., RA Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., RA Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., RA Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., RA Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., RA Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., RA Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., RA Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., RA Rogers J., Ross M.T.; RT "The DNA sequence and analysis of human chromosome 13."; RL Nature 428:522-528(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lymph; 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 FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=8440384; DOI=10.1016/0014-5793(93)80528-3; RA Mancini J.A., Abramovitz M., Cox M.E., Wong E., Charleson S., Perrier H., RA Wang Z., Prasit P., Vickers P.J.; RT "5-lipoxygenase-activating protein is an arachidonate binding protein."; RL FEBS Lett. 318:277-281(1993). RN [7] RP SUBCELLULAR LOCATION. RX PubMed=8245774; DOI=10.1084/jem.178.6.1935; RA Woods J.W., Evans J.F., Ethier D., Scott S., Vickers P.J., Hearn L., RA Heibein J.A., Charleson S., Singer I.I.; RT "5-lipoxygenase and 5-lipoxygenase-activating protein are localized in the RT nuclear envelope of activated human leukocytes."; RL J. Exp. Med. 178:1935-1946(1993). RN [8] RP SUSCEPTIBILITY TO MYOCARDIAL INFARCTION, AND SUSCEPTIBILITY TO ISCHSTR. RX PubMed=14770184; DOI=10.1038/ng1311; RA Helgadottir A., Manolescu A., Thorleifsson G., Gretarsdottir S., RA Jonsdottir H., Thorsteinsdottir U., Samani N.J., Gudmundsson G., RA Grant S.F.A., Thorgeirsson G., Sveinbjornsdottir S., Valdimarsson E.M., RA Matthiasson S.E., Johannsson H., Gudmundsdottir O., Gurney M.E., Sainz J., RA Thorhallsdottir M., Andresdottir M., Frigge M.L., Topol E.J., Kong A., RA Gudnason V., Hakonarson H., Gulcher J.R., Stefansson K.; RT "The gene encoding 5-lipoxygenase activating protein confers risk of RT myocardial infarction and stroke."; RL Nat. Genet. 36:233-239(2004). RN [9] RP LACK OF ASSOCIATION WITH MYOCARDIAL INFARCTION. RX PubMed=17304054; DOI=10.1097/gim.0b013e318030c9c5; RA Koch W., Hoppmann P., Mueller J.C., Schomig A., Kastrati A.; RT "No association of polymorphisms in the gene encoding 5-lipoxygenase- RT activating protein and myocardial infarction in a large central European RT population."; RL Genet. Med. 9:123-129(2007). RN [10] RP INTERACTION WITH LTC4S AND ALOX5, AND SUBCELLULAR LOCATION. RX PubMed=19233132; DOI=10.1016/j.bbrc.2009.02.074; RA Strid T., Svartz J., Franck N., Hallin E., Ingelsson B., Soederstroem M., RA Hammarstroem S.; RT "Distinct parts of leukotriene C(4) synthase interact with 5-lipoxygenase RT and 5-lipoxygenase activating protein."; RL Biochem. Biophys. Res. Commun. 381:518-522(2009). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [13] RP X-RAY CRYSTALLOGRAPHY (4.0 ANGSTROMS) IN COMPLEXES WITH LEUKOTRIENE RP BIOSYNTHESIS INHIBITOR MK-591, TOPOLOGY, SUBUNIT, MUTAGENESIS OF VAL-20; RP ALA-27; VAL-30; ASP-62; THR-66; TYR-112; ILE-113; LYS-116 AND PHE-123, AND RP DOMAIN. RX PubMed=17600184; DOI=10.1126/science.1144346; RA Ferguson A.D., McKeever B.M., Xu S., Wisniewski D., Miller D.K., RA Yamin T.-T., Spencer R.H., Chu L., Ujjainwalla F., Cunningham B.R., RA Evans J.F., Becker J.W.; RT "Crystal structure of inhibitor-bound human 5-lipoxygenase-activating RT protein."; RL Science 317:510-512(2007). CC -!- FUNCTION: Required for leukotriene biosynthesis by ALOX5 (5- CC lipoxygenase). Anchors ALOX5 to the membrane. Binds arachidonic acid, CC and could play an essential role in the transfer of arachidonic acid to CC ALOX5. Binds to MK-886, a compound that blocks the biosynthesis of CC leukotrienes. {ECO:0000269|PubMed:2300173, ECO:0000269|PubMed:8440384}. CC -!- SUBUNIT: Homotrimer. Interacts with LTC4S and ALOX5. CC {ECO:0000269|PubMed:17600184, ECO:0000269|PubMed:19233132}. CC -!- INTERACTION: CC P20292; Q13520: AQP6; NbExp=3; IntAct=EBI-3904621, EBI-13059134; CC P20292; O15552: FFAR2; NbExp=3; IntAct=EBI-3904621, EBI-2833872; CC P20292; O15529: GPR42; NbExp=3; IntAct=EBI-3904621, EBI-18076404; CC P20292; Q9H115: NAPB; NbExp=3; IntAct=EBI-3904621, EBI-3921185; CC P20292; P35372-10: OPRM1; NbExp=3; IntAct=EBI-3904621, EBI-12807478; CC P20292; A0PK00: TMEM120B; NbExp=3; IntAct=EBI-3904621, EBI-10171534; CC P20292; Q96FB2; NbExp=3; IntAct=EBI-3904621, EBI-2857623; CC -!- SUBCELLULAR LOCATION: Nucleus membrane; Multi-pass membrane protein. CC Endoplasmic reticulum membrane; Multi-pass membrane protein. CC -!- DOMAIN: The C-terminal part after residue 140 is mostly unstructured. CC {ECO:0000269|PubMed:17600184}. CC -!- DISEASE: Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute CC neurologic event leading to death of neural tissue of the brain and CC resulting in loss of motor, sensory and/or cognitive function. Ischemic CC strokes, resulting from vascular occlusion, is considered to be a CC highly complex disease consisting of a group of heterogeneous disorders CC with multiple genetic and environmental risk factors. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- DISEASE: Note=Genetic variations in ALOX5AP may be associated with CC susceptibility to myocardial infarction. Involvement in myocardial CC infarction is however unclear: according to some authors CC (PubMed:14770184), a 4-SNP haplotype in ALOX5AP confers risk of CC myocardial infarction, while according to other (PubMed:17304054) CC ALOX5AP is not implicated in this condition. CC {ECO:0000269|PubMed:14770184, ECO:0000269|PubMed:17304054}. CC -!- SIMILARITY: Belongs to the MAPEG family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/alox5ap/"; 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; X52195; CAA36441.1; -; mRNA. DR EMBL; M63262; AAA35845.1; -; Genomic_DNA. DR EMBL; M60470; AAA35845.1; JOINED; Genomic_DNA. DR EMBL; M63259; AAA35845.1; JOINED; Genomic_DNA. DR EMBL; M63260; AAA35845.1; JOINED; Genomic_DNA. DR EMBL; AY619687; AAT38104.1; -; Genomic_DNA. DR EMBL; AL512642; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC018538; AAH18538.1; -; mRNA. DR CCDS; CCDS9337.1; -. DR PIR; A39824; A39824. DR RefSeq; NP_001191335.1; NM_001204406.1. DR RefSeq; NP_001620.2; NM_001629.3. DR PDB; 2Q7M; X-ray; 4.25 A; A/B/C/D/E/F=1-161. DR PDB; 2Q7R; X-ray; 4.00 A; A/B/C/D/E/F=1-161. DR PDB; 6VGC; X-ray; 2.37 A; A/B/C/D/E/F=2-161. DR PDB; 6VGI; X-ray; 2.61 A; A/B/C/D/E/F=2-161. DR PDBsum; 2Q7M; -. DR PDBsum; 2Q7R; -. DR PDBsum; 6VGC; -. DR PDBsum; 6VGI; -. DR AlphaFoldDB; P20292; -. DR SMR; P20292; -. DR BioGRID; 106742; 14. DR IntAct; P20292; 9. DR STRING; 9606.ENSP00000479870; -. DR BindingDB; P20292; -. DR ChEMBL; CHEMBL4550; -. DR DrugBank; DB05225; AM103. DR DrugBank; DB04929; DG031. DR DrugBank; DB06346; Fiboflapon. DR DrugBank; DB16739; MK-886. DR DrugBank; DB16346; Veliflapon. DR DrugCentral; P20292; -. DR GlyGen; P20292; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; P20292; -. DR PhosphoSitePlus; P20292; -. DR BioMuta; ALOX5AP; -. DR DMDM; 120267; -. DR jPOST; P20292; -. DR MassIVE; P20292; -. DR MaxQB; P20292; -. DR PaxDb; 9606-ENSP00000479870; -. DR PeptideAtlas; P20292; -. DR ProteomicsDB; 53744; -. DR Pumba; P20292; -. DR TopDownProteomics; P20292; -. DR Antibodypedia; 22770; 233 antibodies from 32 providers. DR DNASU; 241; -. DR Ensembl; ENST00000380490.5; ENSP00000369858.3; ENSG00000132965.10. DR GeneID; 241; -. DR KEGG; hsa:241; -. DR MANE-Select; ENST00000380490.5; ENSP00000369858.3; NM_001629.4; NP_001620.2. DR UCSC; uc001utf.3; human. DR AGR; HGNC:436; -. DR CTD; 241; -. DR DisGeNET; 241; -. DR GeneCards; ALOX5AP; -. DR HGNC; HGNC:436; ALOX5AP. DR HPA; ENSG00000132965; Group enriched (bone marrow, lung, lymphoid tissue). DR MalaCards; ALOX5AP; -. DR MIM; 601367; phenotype. DR MIM; 603700; gene. DR neXtProt; NX_P20292; -. DR OpenTargets; ENSG00000132965; -. DR PharmGKB; PA47; -. DR VEuPathDB; HostDB:ENSG00000132965; -. DR eggNOG; ENOG502RZJB; Eukaryota. DR GeneTree; ENSGT00940000158706; -. DR HOGENOM; CLU_110291_0_0_1; -. DR InParanoid; P20292; -. DR OMA; QNVFFAQ; -. DR OrthoDB; 5343039at2759; -. DR PhylomeDB; P20292; -. DR TreeFam; TF105328; -. DR BioCyc; MetaCyc:ENSG00000132965-MONOMER; -. DR PathwayCommons; P20292; -. DR Reactome; R-HSA-2142688; Synthesis of 5-eicosatetraenoic acids. DR Reactome; R-HSA-2142691; Synthesis of Leukotrienes (LT) and Eoxins (EX). DR Reactome; R-HSA-2142700; Synthesis of Lipoxins (LX). DR SignaLink; P20292; -. DR BioGRID-ORCS; 241; 13 hits in 1153 CRISPR screens. DR ChiTaRS; ALOX5AP; human. DR EvolutionaryTrace; P20292; -. DR GeneWiki; 5-lipoxygenase-activating_protein; -. DR GenomeRNAi; 241; -. DR Pharos; P20292; Tchem. DR PRO; PR:P20292; -. DR Proteomes; UP000005640; Chromosome 13. DR RNAct; P20292; Protein. DR Bgee; ENSG00000132965; Expressed in blood and 168 other cell types or tissues. DR ExpressionAtlas; P20292; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005635; C:nuclear envelope; IDA:UniProtKB. DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB. DR GO; GO:0004051; F:arachidonate 5-lipoxygenase activity; IEA:Ensembl. DR GO; GO:0050544; F:arachidonic acid binding; IDA:UniProtKB. DR GO; GO:0008047; F:enzyme activator activity; IEA:InterPro. DR GO; GO:0019899; F:enzyme binding; IEA:Ensembl. DR GO; GO:0004602; F:glutathione peroxidase activity; IBA:GO_Central. DR GO; GO:0004364; F:glutathione transferase activity; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl. DR GO; GO:0004464; F:leukotriene-C4 synthase activity; IBA:GO_Central. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0071277; P:cellular response to calcium ion; IDA:UniProtKB. DR GO; GO:0019370; P:leukotriene biosynthetic process; IDA:UniProtKB. DR GO; GO:0002540; P:leukotriene production involved in inflammatory response; IEA:Ensembl. DR GO; GO:0019372; P:lipoxygenase pathway; IEA:Ensembl. DR GO; GO:0002675; P:positive regulation of acute inflammatory response; IEA:Ensembl. DR GO; GO:0070207; P:protein homotrimerization; IPI:UniProtKB. DR Gene3D; 1.20.120.550; Membrane associated eicosanoid/glutathione metabolism-like domain; 1. DR InterPro; IPR001446; 5_LipOase_AP. DR InterPro; IPR018295; FLAP/GST2/LTC4S_CS. DR InterPro; IPR023352; MAPEG-like_dom_sf. DR InterPro; IPR001129; Membr-assoc_MAPEG. DR PANTHER; PTHR10250:SF2; ARACHIDONATE 5-LIPOXYGENASE-ACTIVATING PROTEIN; 1. DR PANTHER; PTHR10250; MICROSOMAL GLUTATHIONE S-TRANSFERASE; 1. DR Pfam; PF01124; MAPEG; 1. DR PRINTS; PR00488; 5LPOXGNASEAP. DR SUPFAM; SSF161084; MAPEG domain-like; 1. DR PROSITE; PS01297; FLAP_GST2_LTC4S; 1. DR Genevisible; P20292; HS. PE 1: Evidence at protein level; KW 3D-structure; Endoplasmic reticulum; Leukotriene biosynthesis; Membrane; KW Nucleus; Reference proteome; Transmembrane; Transmembrane helix. FT CHAIN 1..161 FT /note="Arachidonate 5-lipoxygenase-activating protein" FT /id="PRO_0000217751" FT TOPO_DOM 1..8 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:17600184" FT TRANSMEM 9..30 FT /note="Helical" FT TOPO_DOM 31..52 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:17600184" FT TRANSMEM 53..77 FT /note="Helical" FT TOPO_DOM 78..80 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:17600184" FT TRANSMEM 81..102 FT /note="Helical" FT TOPO_DOM 103..107 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:17600184" FT INTRAMEM 108..115 FT TRANSMEM 116..128 FT /note="Helical" FT TOPO_DOM 129..161 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:17600184" FT MUTAGEN 20 FT /note="V->A: Increased affinity for the inhibitor MK-591." FT /evidence="ECO:0000269|PubMed:17600184" FT MUTAGEN 27 FT /note="A->V: Strongly decreased affinity for the inhibitor FT MK-591." FT /evidence="ECO:0000269|PubMed:17600184" FT MUTAGEN 30 FT /note="V->A: Strongly decreased affinity for the inhibitor FT MK-591." FT /evidence="ECO:0000269|PubMed:17600184" FT MUTAGEN 62 FT /note="D->A: Decreased affinity for the inhibitor MK-591." FT /evidence="ECO:0000269|PubMed:17600184" FT MUTAGEN 66 FT /note="T->A: Strongly decreased affinity for the inhibitor FT MK-591." FT /evidence="ECO:0000269|PubMed:17600184" FT MUTAGEN 112 FT /note="Y->A: Strongly decreased affinity for the inhibitor FT MK-591." FT /evidence="ECO:0000269|PubMed:17600184" FT MUTAGEN 113 FT /note="I->A: Increased affinity for the inhibitor MK-591." FT /evidence="ECO:0000269|PubMed:17600184" FT MUTAGEN 116 FT /note="K->A: Strongly increased affinity for the inhibitor FT MK-591." FT /evidence="ECO:0000269|PubMed:17600184" FT MUTAGEN 123 FT /note="F->A: Decreased affinity for the inhibitor MK-591." FT /evidence="ECO:0000269|PubMed:17600184" FT CONFLICT 161 FT /note="P -> S (in Ref. 1; CAA36441)" FT /evidence="ECO:0000305" FT HELIX 3..7 FT /evidence="ECO:0007829|PDB:6VGC" FT HELIX 10..34 FT /evidence="ECO:0007829|PDB:6VGC" FT HELIX 48..77 FT /evidence="ECO:0007829|PDB:6VGC" FT HELIX 80..101 FT /evidence="ECO:0007829|PDB:6VGC" FT HELIX 116..153 FT /evidence="ECO:0007829|PDB:6VGC" FT HELIX 155..157 FT /evidence="ECO:0007829|PDB:6VGI" SQ SEQUENCE 161 AA; 18157 MW; 2625F8081B9E1BAA CRC64; MDQETVGNVV LLAIVTLISV VQNGFFAHKV EHESRTQNGR SFQRTGTLAF ERVYTANQNC VDAYPTFLAV LWSAGLLCSQ VPAAFAGLMY LFVRQKYFVG YLGERTQSTP GYIFGKRIIL FLFLMSVAGI FNYYLIFFFG SDFENYIKTI STTISPLLLI P //