AL5AP_HUMAN
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 03-AUG-2022, entry version 180.
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 DrugCentral; P20292; -.
DR GlyGen; P20292; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P20292; -.
DR PhosphoSitePlus; P20292; -.
DR BioMuta; ALOX5AP; -.
DR DMDM; 120267; -.
DR jPOST; P20292; -.
DR MassIVE; P20292; -.
DR MaxQB; P20292; -.
DR PaxDb; P20292; -.
DR PeptideAtlas; P20292; -.
DR PRIDE; P20292; -.
DR ProteomicsDB; 53744; -.
DR TopDownProteomics; P20292; -.
DR Antibodypedia; 22770; 223 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 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; 1609516at2759; -.
DR PhylomeDB; P20292; -.
DR TreeFam; TF105328; -.
DR BioCyc; MetaCyc:ENSG00000132965-MON; -.
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; 12 hits in 1073 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 166 other tissues.
DR ExpressionAtlas; P20292; baseline and differential.
DR Genevisible; P20292; HS.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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:0047485; F:protein N-terminus binding; IPI:UniProtKB.
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; -; 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 Pfam; PF01124; MAPEG; 1.
DR PRINTS; PR00488; 5LPOXGNASEAP.
DR SUPFAM; SSF161084; SSF161084; 1.
DR PROSITE; PS01297; FLAP_GST2_LTC4S; 1.
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
