P06727 (APOA4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Apolipoprotein A-IV
Short name=Apo-AIV
Short name=ApoA-IV

Alternative name(s):
Apolipoprotein A4

Gene names

Name:

APOA4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	396 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	May have a role in chylomicrons and VLDL secretion and catabolism. Required for efficient activation of lipoprotein lipase by ApoC-II; potent activator of LCAT. Apoa-IV is a major component of HDL and chylomicrons.
Subcellular location	Secreted.
Tissue specificity	Synthesized primarily in the intestine and secreted in plasma.
Domain	Nine of the thirteen 22-amino acid tandem repeats (each 22-mer is actually a tandem array of two, A and B, related 11-mers) occurring in this sequence are predicted to be highly alpha-helical, and many of these helices are amphipathic. They may therefore serve as lipid-binding domains with lecithin:cholesterol acyltransferase (LCAT) activating abilities.
Post-translational modification	Phosphorylation sites are present in the extracellular medium.
Polymorphism	Eight alleles have been characterized (APOA-IV*0 to APOA-IV*7). APOA-IV*1 is the major allele (90%), APOA-IV*2 is also common (8%), the others are rare alleles. The sequence shown represents allele APOA-IV*1.
Sequence similarities	Belongs to the apolipoprotein A1/A4/E family.

Ontologies

Keywords
Biological process	Lipid transport Transport
Cellular component	Chylomicron HDL Secreted
Coding sequence diversity	Polymorphism
Domain	Repeat Signal
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cholesterol efflux Inferred from direct assay PubMed 11162594PubMed 1935934. Source: BHF-UCL cholesterol homeostasis Inferred from direct assay PubMed 1935934. Source: BHF-UCL cholesterol metabolic process Inferred from direct assay PubMed 1935934. Source: BHF-UCL chylomicron assembly Traceable author statement PubMed 16159879. Source: BHF-UCL chylomicron remodeling Inferred by curator PubMed 2307668. Source: BHF-UCL high-density lipoprotein particle remodeling Inferred by curator PubMed 1935934. Source: BHF-UCL hydrogen peroxide catabolic process Inferred from direct assay PubMed 16945374. Source: HGNC innate immune response in mucosa Inferred from direct assay PubMed 15254593. Source: BHF-UCL leukocyte cell-cell adhesion Inferred from direct assay PubMed 15254593. Source: BHF-UCL lipoprotein metabolic process Traceable author statement. Source: Reactome multicellular organismal lipid catabolic process Inferred from direct assay PubMed 3095477. Source: BHF-UCL negative regulation of plasma lipoprotein particle oxidation Inferred from direct assay PubMed 16945374. Source: BHF-UCL phosphatidylcholine metabolic process Inferred from direct assay PubMed 1935934. Source: BHF-UCL phospholipid efflux Inferred from direct assay PubMed 11162594. Source: BHF-UCL positive regulation of cholesterol esterification Inferred from direct assay PubMed 1935934. Source: BHF-UCL positive regulation of fatty acid biosynthetic process Inferred from direct assay PubMed 2307668. Source: BHF-UCL positive regulation of lipoprotein lipase activity Inferred from direct assay PubMed 2307668. Source: BHF-UCL positive regulation of triglyceride catabolic process Inferred from direct assay PubMed 2307668. Source: BHF-UCL regulation of cholesterol transport Inferred from direct assay PubMed 11940599. Source: BHF-UCL regulation of intestinal cholesterol absorption Inferred from electronic annotation. Source: Compara removal of superoxide radicals Inferred from direct assay PubMed 16945374. Source: HGNC response to lipid hydroperoxide Inferred from direct assay PubMed 16945374. Source: HGNC response to stilbenoid Inferred from electronic annotation. Source: Compara reverse cholesterol transport Inferred from direct assay PubMed 3095477. Source: BHF-UCL very-low-density lipoprotein particle remodeling Inferred from direct assay PubMed 2307668. Source: BHF-UCL
Cellular_component	chylomicron Inferred from direct assay PubMed 3095477. Source: BHF-UCL endoplasmic reticulum lumen Traceable author statement. Source: Reactome high-density lipoprotein particle Inferred from direct assay PubMed 3095477. Source: BHF-UCL very-low-density lipoprotein particle Inferred from direct assay PubMed 17154273PubMed 3095477. Source: BHF-UCL
Molecular_function	antioxidant activity Inferred from direct assay PubMed 16945374. Source: HGNC cholesterol transporter activity Inferred from direct assay PubMed 1935934. Source: BHF-UCL copper ion binding Inferred from direct assay PubMed 16945374. Source: HGNC phosphatidylcholine binding Inferred from direct assay PubMed 11940599PubMed 1935934. Source: BHF-UCL phosphatidylcholine-sterol O-acyltransferase activator activity Inferred from direct assay PubMed 1935934. Source: BHF-UCL protein homodimerization activity Inferred from direct assay PubMed 1935934. Source: BHF-UCL
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 20

20

Chain

21 – 396

376

Apolipoprotein A-IV

PRO_0000001975

Regions

Repeat

33 – 54

22

1

Repeat

60 – 81

22

2

Repeat

82 – 103

22

3

Repeat

115 – 136

22

4

Repeat

137 – 158

22

5

Repeat

159 – 180

22

6

Repeat

181 – 202

22

7

Repeat

203 – 224

22

8

Repeat

225 – 246

22

9

Repeat

247 – 268

22

10

Repeat

269 – 286

18

11

Repeat

287 – 308

22

12

Repeat

309 – 330

22

13

Region

33 – 330

298

13 X 22 AA approximate tandem repeats

Compositional bias

372 – 389

18

Gln/Glu-rich

Natural variations

Natural variant

13

1

V → M in allele APOA-IV*1D. Ref.5 Ref.17

VAR_000626

Natural variant

44

1

E → K in Budapest-2. Ref.20

VAR_000627

Natural variant

74

1

G → S.
Corresponds to variant rs5102 [ dbSNP | Ensembl ].

VAR_014610

Natural variant

77

1

Q → H. Ref.5

VAR_025444

Natural variant

147

1

N → S in allele APOA-IV*1B. Ref.5 Ref.6 Ref.18
Corresponds to variant rs5104 [ dbSNP | Ensembl ].

VAR_000628

Natural variant

161

1

A → S in Seattle-3. Ref.5 Ref.21

VAR_000629

Natural variant

178

1

S → L in Seattle-1; may contribute to the development of familial combined hyperlipidemia. Ref.21

VAR_000630

Natural variant

185

1

E → K in allele APOA-IV*3. Ref.15

VAR_000631

Natural variant

187

1

K → E in allele APOA-IV*0A; associated with H-380. Ref.15

VAR_000632

Natural variant

250

1

E → K in allele APOA-IV*3A. Ref.12

VAR_000633

Natural variant

264

1

R → Q in Seattle-2; may contribute to the development of familial combined hyperlipidemia. Ref.21
Corresponds to variant rs2238008 [ dbSNP | Ensembl ].

VAR_000634

Natural variant

279

1

R → K. Ref.1 Ref.2
Corresponds to variant rs1042372 [ dbSNP | Ensembl ].

VAR_025443

Natural variant

305

1

R → C in Budapest-1. Ref.20

VAR_000635

Natural variant

307

1

V → L.
Corresponds to variant rs5108 [ dbSNP | Ensembl ].

VAR_014611

Natural variant

367

1

T → S in allele APOA-IV*1A and allele Budapest-1. Ref.5 Ref.15 Ref.20
Corresponds to variant rs675 [ dbSNP | Ensembl ].

VAR_000636

Natural variant

380

1

Q → H in allele APOA-IV*2 and allele APOA-IV*0A; associated with E-187 in allele APOA-IV*0A. Ref.3 Ref.5 Ref.8 Ref.11 Ref.14 Ref.15 Ref.22
Corresponds to variant rs5110 [ dbSNP | Ensembl ].

VAR_000637

Natural variant

381

1

Q → QEQQQ in allele APOA-IV*0 and allele APOA-IV*5; allele APOA-IV*5 is further defined by a silent nucleotide substitution.

VAR_000638

Experimental info

Sequence conflict

158 – 160

3

TPY → DPL in AAA51744. Ref.1

Sequence conflict

158 – 160

3

TPY → DPL in AAA51745. Ref.2

Sequence conflict

327

1

Q → T in AAA96731. Ref.3

Sequence conflict

327

1

Q → T in AAA51748. Ref.8

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

396

Helix Strand Turn

Details...

Helix

97 – 113

17

Helix

114 – 116

3

Helix

117 – 223

107

Helix

224 – 226

3

Helix

231 – 276

46

Beta strand

278 – 280

3

Helix

282 – 307

26

Helix

310 – 329

20

Sequences

	Sequence		Length	Mass (Da)
	P06727 [UniParc]. Last modified March 7, 2006. Version 3. Checksum: 193753196CA2FA4A	FASTA	396	45,399
	10 20 30 40 50 60 MFLKAVVLTL ALVAVAGARA EVSADQVATV MWDYFSQLSN NAKEAVEHLQ KSELTQQLNA 70 80 90 100 110 120 LFQDKLGEVN TYAGDLQKKL VPFATELHER LAKDSEKLKE EIGKELEELR ARLLPHANEV 130 140 150 160 170 180 SQKIGDNLRE LQQRLEPYAD QLRTQVNTQA EQLRRQLTPY AQRMERVLRE NADSLQASLR 190 200 210 220 230 240 PHADELKAKI DQNVEELKGR LTPYADEFKV KIDQTVEELR RSLAPYAQDT QEKLNHQLEG 250 260 270 280 290 300 LTFQMKKNAE ELKARISASA EELRQRLAPL AEDVRGNLRG NTEGLQKSLA ELGGHLDQQV 310 320 330 340 350 360 EEFRRRVEPY GENFNKALVQ QMEQLRQKLG PHAGDVEGHL SFLEKDLRDK VNSFFSTFKE 370 380 390 KESQDKTLSL PELEQQQEQQ QEQQQEQVQM LAPLES

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Structure, evolution, and tissue-specific synthesis of human apolipoprotein AIV." Karathanasis S.K., Yunis I. Biochemistry 25:3962-3970(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT LYS-279.
[2]	"Structure, evolution, and polymorphisms of the human apolipoprotein A4 gene (APOA4)." Karathanasis S.K., Oettgen P., Haddad I.A., Antonarakis S.E. Proc. Natl. Acad. Sci. U.S.A. 83:8457-8461(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT LYS-279.
[3]	"Structure and expression of the human apolipoprotein A-IV gene." Elshourbagy N.A., Walker D.W., Paik Y.K., Boguski M.S., Freeman M., Gordon J.I., Taylor J.M. J. Biol. Chem. 262:7973-7981(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT APOA-IV*2 HIS-380.
[4]	"The primary structure of human apolipoprotein A-IV." Yang C., Gu Z.W., Xiong W., Rosseneu M., Yang H.X., Lee B.M., Gotto A.M. Jr., Chan L. Biochim. Biophys. Acta 1002:231-237(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Intestine.
[5]	"The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster." Fullerton S.M., Buchanan A.V., Sonpar V.A., Taylor S.L., Smith J.D., Carlson C.S., Salomaa V., Stengaard J.H., Boerwinkle E., Clark A.G., Nickerson D.A., Weiss K.M. Hum. Genet. 115:36-56(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS MET-13; HIS-77; SER-147; SER-161; SER-367 AND HIS-380.
[6]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT SER-147.
[7]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain and Colon.
[8]	"The nucleotide and derived amino acid sequence of human apolipoprotein A-IV mRNA and the close linkage of its gene to the genes of apolipoproteins A-I and C-III." Elshourbagy N.A., Walker D.W., Boguski M.S., Gordon J.I., Taylor J.M. J. Biol. Chem. 261:1998-2002(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 21-396, VARIANT APOA-IV*2 HIS-380.
[9]	"Biosynthesis of human preapolipoprotein A-IV." Gordon J.I., Bisgaier C.L., Sims H.F., Sachdev O.P., Glickman R.M., Strauss A.W. J. Biol. Chem. 259:468-474(1984) [PubMed] [Europe PMC] [Abstract] Cited for: SIGNAL SEQUENCE CLEAVAGE SITE.
[10]	"Genetic polymorphism of apolipoprotein A-IV." Lohse P., Brewer H.B. Jr. Curr. Opin. Lipidol. 2:90-95(1991) Cited for: REVIEW ON POLYMORPHISM.
[11]	"Genetic polymorphism of human plasma apolipoprotein A-IV is due to nucleotide substitutions in the apolipoprotein A-IV gene." Lohse P., Kindt M.R., Rader D.J., Brewer H.B. Jr. J. Biol. Chem. 265:10061-10064(1990) [PubMed] [Europe PMC] [Abstract] Cited for: ALLELES APOA-IV*1 AND APOA-IV*2, VARIANT HIS-380.
[12]	"Human plasma apolipoproteins A-IV-0 and A-IV-3. Molecular basis for two rare variants of apolipoprotein A-IV-1." Lohse P., Kindt M.R., Rader D.J., Brewer H.B. Jr. J. Biol. Chem. 265:12734-12739(1990) [PubMed] [Europe PMC] [Abstract] Cited for: ALLELES A-IV*0 AND A-IV*3, VARIANTS LYS-250 AND GLU-GLN-GLN-GLN-381 INS.
[13]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[14]	"The mutation causing the common apolipoprotein A-IV polymorphism is a glutamine to histidine substitution of amino acid 360." Tenkanen H., Lukka M., Jauhiainen M., Metso J., Baumann M., Peltonen L., Ehnholm C. Arterioscler. Thromb. 11:851-856(1991) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HIS-380.
[15]	"Three genetic variants of human plasma apolipoprotein A-IV: apoA-IV-1(Thr-347-->Ser), apoA-IV-0(Lys-167-->Glu,Gln-360-->His), and apoA-IV-3(Glu-165-->Lys)." Lohse P., Kindt M.R., Rader D.J., Brewer H.B. Jr. J. Biol. Chem. 266:13513-13518(1991) [PubMed] [Europe PMC] [Abstract] Cited for: ALLELES A-IV*0; A-IV*1; A-IV*2 AND A-IV*3, VARIANTS LYS-185; GLU-187; SER-367 AND HIS-380.
[16]	Erratum Lohse P., Kindt M.R., Rader D.J., Brewer H.B. Jr. J. Biol. Chem. 266:19866-19866(1991)
[17]	"Nonsynonymous polymorphic sites in the apolipoprotein (apo) A-IV gene are associated with changes in the concentration of apo B- and apo A-I-containing lipoproteins in a normal population." von Eckardstein A., Funke H., Schulte M., Erren M., Schulte H., Assmann G. Am. J. Hum. Genet. 50:1115-1128(1992) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MET-13.
[18]	"A novel polymorphism of apolipoprotein A-IV is the result of an asparagine to serine substitution at residue 127." Tenkanen H., Koskinen P., Metso J., Baumann M., Lukka M., Kauppinen-Makelin R., Kontula K., Taskinen M.R., Manttari M., Manninen V., Ehnholm C. Biochim. Biophys. Acta 1138:27-33(1992) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SER-147.
[19]	"Molecular basis of a unique African variant (A-IV 5) of human apolipoprotein A-IV and its significance in lipid metabolism." Kamboh M.I., Williams E.R., Law J.C., Aston C.E., Bunker C.H., Ferrell R.E., Pollitzer W.S. Genet. Epidemiol. 9:379-388(1992) [PubMed] [Europe PMC] [Abstract] Cited for: ALLELE A-IV*5, VARIANT GLU-GLN-GLN-GLN-381 INS.
[20]	"Apolipoprotein A-IV polymorphism in the Hungarian population: gene frequencies, effect on lipid levels, and sequence of two new variants." Menzel H.J., Dieplinger H., Sandholzer C., Karadi I., Utermann G., Csaszar A. Hum. Mutat. 5:58-65(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS BUDAPEST-2 LYS-44; BUDAPEST-1 CYS-305 AND SER-367.
[21]	"Two novel apolipoprotein A-IV variants in individuals with familial combined hyperlipidemia and diminished levels of lipoprotein lipase activity." Deeb S.S., Nevin D.N., Iwasaki L., Brunzell J.D. Hum. Mutat. 8:319-325(1996) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS SEATTLE-3 SER-161; SEATTLE-1 LEU-178 AND SEATTLE-2 GLN-264.
[22]	"Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis." Halushka M.K., Fan J.-B., Bentley K., Hsie L., Shen N., Weder A., Cooper R., Lipshutz R., Chakravarti A. Nat. Genet. 22:239-247(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HIS-380.
+	Additional computationally mapped references.

Web resources

SHMPD

The Singapore human mutation and polymorphism database

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M13654 mRNA. Translation: AAA51744.1.
M14642 Genomic DNA. Translation: AAA51745.1.
J02758 Genomic DNA. Translation: AAA96731.1.
X13629 mRNA. Translation: CAA31955.1.
AY422950 Genomic DNA. Translation: AAQ91809.1.
AY555191 Genomic DNA. Translation: AAS68228.1.
AP006216 Genomic DNA. No translation available.
BC074764 mRNA. Translation: AAH74764.1.
BC113594 mRNA. Translation: AAI13595.1.
BC113596 mRNA. Translation: AAI13597.1.
M14566 mRNA. Translation: AAA51748.1.

IPI

IPI00304273.

PIR

LPHUA4. A94137.

UniGene

Hs.1247.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3S84	X-ray	2.40	A/B	84-355	[»]

ProteinModelPortal

P06727.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-38333N.

IntAct

P06727. 1 interaction.

STRING

9606.ENSP00000350425.

PTM databases

PhosphoSite

P06727.

Polymorphism databases

DMDM

93163358.

2D gel databases

DOSAC-COBS-2DPAGE

P06727.

REPRODUCTION-2DPAGE

IPI00304273.

SWISS-2DPAGE

P06727.

Proteomic databases

PaxDb

P06727.

PeptideAtlas

P06727.

PRIDE

P06727.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000357780; ENSP00000350425; ENSG00000110244.

UCSC

uc001pps.1. human.

Organism-specific databases

GeneCards

GC11M116692.

HGNC

HGNC:602. APOA4.

HPA

HPA001352.
HPA002549.

MIM

107690. gene.

neXtProt

NX_P06727.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG42418.

HOGENOM

HOG000037942.

HOVERGEN

HBG105707.

InParanoid

P06727.

OrthoDB

EOG4G1MHJ.

PhylomeDB

P06727.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.
REACT_116125. Disease.

Gene expression databases

Bgee

P06727.

CleanEx

HS_APOA4.

Genevestigator

P06727.

GermOnline

ENSG00000110244. Homo sapiens.

Family and domain databases

InterPro

IPR013326. ApoA.
IPR000074. ApoA1_A4_E.
[Graphical view]

Pfam

PF01442. Apolipoprotein. 2 hits.
[Graphical view]

SUPFAM

SSF47162. SSF47162. 3 hits.

ProtoNet

Search...

Other

PMAP-CutDB

A8MSL6.

SOURCE

Search...

Entry information

Entry name

APOA4_HUMAN

Accession

Primary (citable) accession number: P06727
Secondary accession number(s): A8MSL6, Q14CW8, Q6Q787

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 1, 1988
Last sequence update:	March 7, 2006
Last modified:	May 1, 2013
This is version 152 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.