Reviewed, UniProtKB/Swiss-Prot P20292 (AL5AP_HUMAN)

Names and origin

Protein names

Recommended name:
    Arachidonate 5-lipoxygenase-activating protein
Alternative name(s):
    FLAP
    MK-886-binding protein

Gene names

Name:	ALOX5AP
Synonyms:	FLAP

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	161 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Required for leukotriene biosynthesis by ALOX5 (5-lipoxygenase). Anchors ALOX5 to the membrane. Binds arachidonic acid, and could play an essential role in the transfer of arachidonic acid to ALOX5. Binds to MK-886, a compound that blocks the biosynthesis of leukotrienes.
Subunit structure	Homotrimer. Interacts with LTC4S and ALOX5.
Subcellular location	Nucleus membrane; Multi-pass membrane protein. Endoplasmic reticulum membrane; Multi-pass membrane protein.
Domain	The C-terminal part after residue 140 is mostly unstructured.
Involvement in disease	Genetic variations in ALOX5AP may be a cause of susceptibility to ischemic stroke [MIM:601367]; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. Haplotypes HapA and HapB are associated with susceptibility to myocardial infarction [MIM:608557].
Sequence similarities	Belongs to the MAPEG family.

Ontologies

Keywords
Biological process	Leukotriene biosynthesis
Cellular component	Endoplasmic reticulum Membrane Nucleus
Domain	Transmembrane
Technical term	3D-structure
Gene Ontology (GO)
Biological process	leukotriene biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW protein homotrimerization Ref.11 Inferred from physical interaction. Source: UniProtKB
Cellular component	endoplasmic reticulum Ref.10 Inferred from direct assay. Source: UniProtKB integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW nuclear membrane Ref.7 Inferred from direct assay. Source: UniProtKB
Molecular function	arachidonic acid binding Inferred from direct assay. Source: UniProtKB enzyme activator activity Inferred from electronic annotation. Source: InterPro protein N-terminus binding Ref.10 Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 161

161

Arachidonate 5-lipoxygenase-activating protein

PRO_0000217751

Regions

Topological domain

1 – 8

8

Lumenal

Transmembrane

9 – 30

22

Topological domain

31 – 52

22

Cytoplasmic

Transmembrane

53 – 77

25

Topological domain

78 – 80

3

Lumenal

Transmembrane

81 – 102

22

Topological domain

103 – 107

5

Cytoplasmic

Topological domain

108 – 115

8

In membrane

Transmembrane

116 – 128

13

Topological domain

129 – 161

33

Lumenal

Region

20 – 27

8

Inhibitor binding

Region

112 – 123

12

Inhibitor binding

Experimental info

Mutagenesis

20

1

V → A: Increased affinity for the inhibitor MK-591.

Mutagenesis

27

1

A → V: Strongly decreased affinity for the inhibitor MK-591.

Mutagenesis

30

1

V → A: Strongly decreased affinity for the inhibitor MK-591.

Mutagenesis

62

1

D → A: Decreased affinity for the inhibitor MK-591.

Mutagenesis

66

1

T → A: Strongly decreased affinity for the inhibitor MK-591.

Mutagenesis

112

1

Y → A: Strongly decreased affinity for the inhibitor MK-591.

Mutagenesis

113

1

I → A: Increased affinity for the inhibitor MK-591.

Mutagenesis

116

1

K → A: Strongly increased affinity for the inhibitor MK-591.

Mutagenesis

123

1

F → A: Decreased affinity for the inhibitor MK-591.

Sequence conflict

161

1

P → S in CAA36441. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

161

Helix Strand Turn

Details...

Helix

3 – 7

5

Helix

10 – 26

17

Turn

27 – 30

4

Helix

31 – 36

6

Helix

50 – 60

11

Helix

63 – 76

14

Helix

80 – 100

21

Beta strand

103 – 106

4

Helix

116 – 138

23

Sequences

	Sequence		Length	Mass (Da)
	P20292-1 [UniParc]. Last modified December 1, 1992. Version 2. Checksum: 2625F8081B9E1BAA	FASTA	161	18,157
	10 20 30 40 50 60 MDQETVGNVV LLAIVTLISV VQNGFFAHKV EHESRTQNGR SFQRTGTLAF ERVYTANQNC 70 80 90 100 110 120 VDAYPTFLAV LWSAGLLCSQ VPAAFAGLMY LFVRQKYFVG YLGERTQSTP GYIFGKRIIL 130 140 150 160 FLFLMSVAGI FNYYLIFFFG SDFENYIKTI STTISPLLLI P

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis." Dixon R.A.F., Diehl R.E., Opas E., Rands E., Vickers P.J., Evans J.F., Gillard J.W., Miller D.K. Nature 343:282-284(1990) [PubMed: 2300173] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[2]	"Gene characterization and promoter analysis of the human 5-lipoxygenase-activating protein (FLAP)." Kennedy B.P., Diehl R.E., Boie Y., Adam M., Dixon R.A.F. J. Biol. Chem. 266:8511-8516(1991) [PubMed: 1673682] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	SeattleSNPs variation discovery resource Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"The DNA sequence and analysis of human chromosome 13." Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L., Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T. Nature 428:522-528(2004) [PubMed: 15057823] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lymph.
[6]	"5-lipoxygenase-activating protein is an arachidonate binding protein." Mancini J.A., Abramovitz M., Cox M.E., Wong E., Charleson S., Perrier H., Wang Z., Prasit P., Vickers P.J. FEBS Lett. 318:277-281(1993) [PubMed: 8440384] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[7]	"5-lipoxygenase and 5-lipoxygenase-activating protein are localized in the nuclear envelope of activated human leukocytes." Woods J.W., Evans J.F., Ethier D., Scott S., Vickers P.J., Hearn L., Heibein J.A., Charleson S., Singer I.I. J. Exp. Med. 178:1935-1946(1993) [PubMed: 8245774] [Abstract] Cited for: SUBCELLULAR LOCATION.
[8]	"The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke." Helgadottir A., Manolescu A., Thorleifsson G., Gretarsdottir S., Jonsdottir H., Thorsteinsdottir U., Samani N.J., Gudmundsson G., Grant S.F.A., Thorgeirsson G., Sveinbjornsdottir S., Valdimarsson E.M., Matthiasson S.E., Johannsson H., Gudmundsdottir O., Gurney M.E., Sainz J., Thorhallsdottir M. , Andresdottir M., Frigge M.L., Topol E.J., Kong A., Gudnason V., Hakonarson H., Gulcher J.R., Stefansson K. Nat. Genet. 36:233-239(2004) [PubMed: 14770184] [Abstract] Cited for: SUSCEPTIBILITY TO MYOCARDIAL INFARCTION, SUSCEPTIBILITY TO ISCHEMIC STROKE.
[9]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[10]	"Distinct parts of leukotriene C(4) synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein." Strid T., Svartz J., Franck N., Hallin E., Ingelsson B., Soederstroem M., Hammarstroem S. Biochem. Biophys. Res. Commun. 381:518-522(2009) [PubMed: 19233132] [Abstract] Cited for: INTERACTION WITH LTC4S AND ALOX5, SUBCELLULAR LOCATION.
[11]	"Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein." Ferguson A.D., McKeever B.M., Xu S., Wisniewski D., Miller D.K., Yamin T.-T., Spencer R.H., Chu L., Ujjainwalla F., Cunningham B.R., Evans J.F., Becker J.W. Science 317:510-512(2007) [PubMed: 17600184] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (4.0 ANGSTROMS) IN COMPLEXES WITH LEUKOTRIENE BIOSYNTHESIS INHIBITOR MK-591, TOPOLOGY, SUBUNIT, MUTAGENESIS OF VAL-20; ALA-27; VAL-30; ASP-62; THR-66; TYR-112; ILE-113; LYS-116 AND PHE-123, DOMAIN.
+	Additional computationally mapped references.

Web resources

SeattleSNPs

Cross-references

Sequence databases

EMBLGenBankDDBJ

X52195 mRNA. Translation: CAA36441.1.
M63262 , M60470, M63259, M63260 Genomic DNA. Translation: AAA35845.1.
AY619687 Genomic DNA. Translation: AAT38104.1.
AL512642 Genomic DNA. Translation: CAH74084.1.
BC018538 mRNA. Translation: AAH18538.1.

IPI

IPI00022975.

PIR

A39824.

RefSeq

NP_001620.2.

UniGene

Hs.507658

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2Q7M	X-ray	4.25	A/B/C/D/E/F	1-161	[»]
2Q7R	X-ray	4.00	A/B/C/D/E/F	1-161	[»]

ModBase

Search...

Proteomic databases

PRIDE

P20292.

Genome annotation databases

Ensembl

ENSG00000132965. Homo sapiens. [Contig view]

GeneID

241.

KEGG

hsa:241.

Organism-specific databases

GeneCards

GC13P030207.

H-InvDB

HIX0011211.

HGNC

HGNC:436. ALOX5AP.

MIM

601367. phenotype.
603700. gene.
608557. phenotype.

PharmGKB

PA47.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

P20292.

OMA

P20292. MDQEAVG.

Gene expression databases

ArrayExpress

P20292.

Bgee

P20292.

CleanEx

HS_ALOX5AP.

GermOnline

ENSG00000132965. Homo sapiens.

Family and domain databases

InterPro

IPR001446. 5_LipOase_AP.
IPR018295. FLAP/GST2/LTC4S_CS.
IPR001129. MAPEG.
[Graphical view]

Pfam

PF01124. MAPEG. 1 hit.
[Graphical view]

PRINTS

PR00488. 5LPOXGNASEAP.

PROSITE

PS01297. FLAP_GST2_LTC4S. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

962.

SOURCE

Search...

Entry information

Entry name

AL5AP_HUMAN

Accession

Primary (citable) accession number: P20292
Secondary accession number(s): Q5VV04

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1991
Last sequence update:	December 1, 1992
Last modified:	June 16, 2009
This is version 77 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)