| Apolipoprotein A-I |
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PDB rendering based on 1av1.
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| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
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1AV1, 1GW3, 1GW4, 1ODP, 1ODQ, 1ODR, 2A01, 3K2S, 3R2P, 4V6M
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| Identifiers |
| Symbols |
APOA1 ; MGC117399 |
| External IDs |
OMIM: 107680 MGI: 88049 HomoloGene: 47900 ChEMBL: 5984 GeneCards: APOA1 Gene |
| Gene ontology |
| Molecular function |
• beta-amyloid binding
• protein binding
• phospholipid binding
• phospholipid transporter activity
• high-density lipoprotein particle binding
• cholesterol binding
• cholesterol transporter activity
• enzyme binding
• phosphatidylcholine binding
• apolipoprotein receptor binding
• apolipoprotein A-I receptor binding
• identical protein binding
• chemorepellent activity
• lipase inhibitor activity
• phosphatidylcholine-sterol O-acyltransferase activator activity
• high-density lipoprotein particle receptor binding
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| Cellular component |
• extracellular region
• extracellular space
• nucleus
• early endosome
• endoplasmic reticulum lumen
• cytosol
• plasma membrane
• cell surface
• endocytic vesicle
• cytoplasmic vesicle
• very-low-density lipoprotein particle
• high-density lipoprotein particle
• discoidal high-density lipoprotein particle
• spherical high-density lipoprotein particle
• secretory granule lumen
• chylomicron
• extracellular exosome
• endocytic vesicle lumen
• blood microparticle
• extracellular vesicle
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| Biological process |
• retinoid metabolic process
• regulation of protein phosphorylation
• endothelial cell proliferation
• platelet degranulation
• negative regulation of cytokine secretion involved in immune response
• phosphatidylcholine biosynthetic process
• cholesterol biosynthetic process
• receptor-mediated endocytosis
• transforming growth factor beta receptor signaling pathway
• G-protein coupled receptor signaling pathway
• integrin-mediated signaling pathway
• response to nutrient
• blood coagulation
• phototransduction, visible light
• cholesterol metabolic process
• glucocorticoid metabolic process
• negative regulation of tumor necrosis factor-mediated signaling pathway
• positive regulation of cholesterol esterification
• positive regulation of triglyceride catabolic process
• negative regulation of very-low-density lipoprotein particle remodeling
• peripheral nervous system axon regeneration
• protein oxidation
• peptidyl-methionine modification
• triglyceride catabolic process
• lipid storage
• platelet activation
• regulation of intestinal cholesterol absorption
• cholesterol transport
• adrenal gland development
• organ regeneration
• neuron projection regeneration
• regulation of Cdc42 protein signal transduction
• cholesterol efflux
• phospholipid efflux
• negative regulation of heterotypic cell-cell adhesion
• very-low-density lipoprotein particle remodeling
• high-density lipoprotein particle remodeling
• high-density lipoprotein particle assembly
• high-density lipoprotein particle clearance
• positive regulation of Rho protein signal transduction
• lipoprotein metabolic process
• lipoprotein biosynthetic process
• response to drug
• cholesterol homeostasis
• blood vessel endothelial cell migration
• response to estrogen
• reverse cholesterol transport
• cellular lipid metabolic process
• small molecule metabolic process
• positive regulation of fatty acid biosynthetic process
• negative regulation of interleukin-1 beta secretion
• negative regulation of inflammatory response
• protein stabilization
• negative chemotaxis
• positive regulation of lipoprotein lipase activity
• vitamin transport
• positive regulation of hydrolase activity
• positive regulation of transferase activity
• positive regulation of stress fiber assembly
• transmembrane transport
• phospholipid homeostasis
• negative regulation of lipase activity
• negative regulation of cell adhesion molecule production
• negative regulation of response to cytokine stimulus
• triglyceride homeostasis
• ERK1 and ERK2 cascade
• cholesterol import
• positive regulation of substrate adhesion-dependent cell spreading
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| Sources: Amigo / QuickGO |
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| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
| Entrez |
335 |
11806 |
| Ensembl |
ENSG00000118137 |
ENSMUSG00000032083 |
| UniProt |
P02647 |
Q00623 |
| RefSeq (mRNA) |
NM_000039 |
NM_009692 |
| RefSeq (protein) |
NP_000030 |
NP_033822 |
| Location (UCSC) |
Chr 11:
116.84 – 116.84 Mb |
Chr 9:
46.23 – 46.23 Mb |
| PubMed search |
[1] |
[2] |
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Apolipoprotein A1 is a protein that in humans is encoded by the APOA1 gene.[1][2] It has a specific role in lipid metabolism. Recent report suggest that APOA1 mRNA is regulated by endogenously expressed antisense RNA.[3]
Apolipoprotein A1 is the major protein component of high density lipoprotein (HDL) in plasma. Chylomicrons secreted from the intestinal enterocyte also contain apo A1, but it is quickly transferred to HDL in the bloodstream.[4] The protein promotes fat efflux, including cholesterol, from tissues to the liver for excretion. It is a cofactor for lecithin cholesterolacyltransferase (LCAT) which is responsible for the formation of most plasma cholesteryl esters. Apo A1 was also isolated as a prostacyclin (PGI2) stabilizing factor, and thus may have an anticlotting effect.[5] Defects in the gene encoding it are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis.[6] ApoA1 is often used as a biomarker for prediction of cardiovascular diseases and the ratio apoB- 100/apoA1 has been reported as a stronger predictor for the risk of myocardial infarction than any other lipid measurement.[7] ApoA1 is routinely measured using immunoassays such as ELISA or nephelometry.
Contents
- 1 Structure
- 2 Clinical significance
- 2.1 Activity associated with high HDL-C and protection from heart disease
- 2.2 Novel Haplotypes within apolipoprotein AI-CIII-AIV gene cluster
- 2.3 Role in other diseases
- 2.4 Epistatic impact of apo A1
- 2.5 Factors affecting apo A1 activity
- 3 Interactions
- 3.1 Potential binding partners
- 3.2 Interactive pathway map
- 4 See also
- 5 References
- 6 External links
Structure
The APOA1 gene is located on the 11th chromosome, with its specific location being 11q23-q24. The gene contains 4 exons. [6] APOA1 encodes a 45.4 kDa protein that is composed of 396 amino acids; 21 peptides have been observed through mass spectrometry data.[8][9]
Clinical significance
Activity associated with high HDL-C and protection from heart disease
As a major component of the high-density lipoprotein complex (protective "fat removal" particles), apo A1 helps to clear fats, including cholesterol, from white blood cells within artery walls, making the WBCs less likely to become fat overloaded, transform into foam cells, die and contribute to progressive atheroma. Five of nine men found to carry a mutation (E164X) who were at least 35 years of age had developed premature coronary artery disease.[10] One of four mutants of apo A1 is present in roughly 0.3% of the Japanese population, but is found in 6% of those with low HDL cholesterol levels.
ApoA-1 Milano is a naturally occurring mutant of apo A1, found in a few families in Limone sul Garda, Italy, and, by genetic + church record family tree detective work, traced to a single individual in the 14th century. Described in 1980, it was the first known molecular abnormality of apolipoproteins.[11] Paradoxically, carriers of this mutation have very low HDL-C (HDL-Cholesterol) levels, but no increase in the risk of heart disease, often living to age 100 or older. This unusual observation was what lead Italian investigators to track down what was going on and lead to the discovery of apo A1 Milano (the city, Milano, ~160 KM away, in which the researcher's lab was located). Biochemically, apo A1 contains an extra cysteine bridge, causing it to exist as a homodimer or as a heterodimer with apo A-II. However, the enhanced cardioprotective activity of this mutant (which likely depends on fat & cholesterol efflux) cannot easily be replicated by other cysteine mutants.[12]
Recombinant apo A1 Milano dimers formulated into liposomes can reduce atheromas in animal models by up to 30%.[13] Apo A1 Milano has also been shown in small clinical trials to have a statistically significant effect in reducing (reversing) plaque build-up on arterial walls.[14][15]
In human trials the reversal of plaque build-up was measured over the course of five weeks.[14][16]
Novel Haplotypes within apolipoprotein AI-CIII-AIV gene cluster
Lately, two novel susceptibility haplotypes i.e. P2-S2-X1 and P1-S2-X1 have been discovered in ApoAI-CIII-AIV gene cluster on chromosome 11q23, which confer approximately threefold higher risk of coronary heart disease in normal[17] as well as in the patients having non-insulin diabetes mellitus.[18]
Role in other diseases
A G/A polymorphism in the promoter of the apo A1 gene has been associated with the age at which patients presented with Alzheimer disease.[19] Protection from Alzheimer's disease by apo A1 may rely on a synergistic interaction with alpha-tocopherol.[20] Amyloid deposited in the knee following surgery consists largely of apo A1 secreted from chondrocytes (cartilage cells).[21] A wide variety of amyloidosis symptoms are associated with rare Apo A1 mutants.
Apo A-I binds to lipopolysaccharide or endotoxin, and has a major role in the anti-endotoxin function of HDL.[22]
In one study, a decrease in apo A1 levels was detected in schizophrenia patients' CSF, brain and peripheral tissues.[23]
Epistatic impact of apo A1
Apolipoprotein A1 and APOE interact epistatically to modulate triglyceride levels in coronary heart disease patients. Individually, neither apo A1 nor apo E was found to be associated with triglyceride (TG) levels however, pairwise epistasis (additive x additive model) explored their significant synergistic contributions with raised TG levels (P<0.01). [24]
Factors affecting apo A1 activity
Apo A1 production is decreased by calcitriol, and increased by a drug that antagonizes it.[25]
Exercise or statin treatment may cause an increase in HDL-C levels by inducing apo A1 production, but this depends on the G/A promoter polymorphism.[26]
Interactions
Apolipoprotein A1 has been shown to interact with:
- ABCA1,[27]
- GPLD1[28] and
- PLTP.[29]
Potential binding partners
Apolipoprotein A1 binding precursor, a relative of APOA-1 abbreviated APOA1BP, has a predicted biochemical interaction with Carbohydrate Kinase Domain Containing Protein. The relationship between these two proteins is substantiated by cooccurance across genomes and coexpression.[30] The ortholog of CARKD in E. coli contains a domain not present in any eukaryotic ortholog. This domain has a high sequence identity to APOA1BP. CARKD is a protein of unknown function, and the biochemical basis for this interaction is unknown.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
[[File:
|{{{bSize}}}px|alt=Statin Pathway edit]]
File:StatinPathway_WP430.png
Statin Pathway edit
- ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".
See also
- Apolipoprotein B
- Cardiovascular disease
References
- ^ Breslow JL, Ross D, McPherson J, Williams H, Kurnit D, Nussbaum AL et al. (November 1982). "Isolation and characterization of cDNA clones for human apolipoprotein A1". Proc. Natl. Acad. Sci. U.S.A. 79 (22): 6861–5. doi:10.1073/pnas.79.22.6861. PMC 347233. PMID 6294659.
- ^ Arinami T, Hirano T, Kobayashi K, Yamanouchi Y, Hamaguchi H (June 1990). "Assignment of the apolipoprotein A1 gene to 11q23 based on RFLP in a case with a partial deletion of chromosome 11, del(11)(q23.3----qter)". Hum. Genet. 85 (1): 39–40. doi:10.1007/BF00276323. PMID 1972696.
- ^ Halley P, Kadakkuzha BM, Faghihi MA, Magistri M, Zeier Z, Khorkova O et al. (16 January 2014). "Regulation of the Apolipoprotein Gene Cluster by a Long Noncoding RNA". Cell Reports 6 (1): 222–230. doi:10.1016/j.celrep.2013.12.015. PMID 24388749.
- ^ Wasan KM, Brocks DR, Lee SD, Sachs-Barrable K, Thornton SJ (January 2008). "Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery". Nature Reviews Drug Discovery 7 (1): 84–99. doi:10.1038/nrd2353. PMID 18079757.
- ^ Yui Y, Aoyama T, Morishita H, Takahashi M, Takatsu Y, Kawai C (1988). "Serum prostacyclin stabilizing factor is identical to apolipoprotein A1 (apo A1). A novel function of apo A1". J. Clin. Invest. 82 (3): 803–7. doi:10.1172/JCI113682. PMC 303586. PMID 3047170.
- ^ a b "Entrez Gene: APOA1 apolipoprotein A1".
- ^ McQueen MJ, Hawken S, Wang X, Ounpuu S, Sniderman A, Probstfield J et al. (2008). "Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study". Lancet 372 (9634): 224–33. doi:10.1016/S0140-6736(08)61076-4. PMID 18640459.
- ^ ]Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS et al. (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
- ^ "Apolipoprotein A-IV". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
- ^ Dastani Z, Dangoisse C, Boucher B, Desbiens K, Krimbou L, Dufour R et al. (March 2006). "A novel nonsense apolipoprotein A-I mutation (apoA-I(E136X)) causes low HDL cholesterol in French Canadians". Atherosclerosis 185 (1): 127–36. doi:10.1016/j.atherosclerosis.2005.05.028. PMID 16023124.
- ^ Franceschini G, Sirtori M, Gianfranceschi G, Sirtori CR (May 1981). "Relation between the HDL apoproteins and A-I isoproteins in subjects with the AIMilano abnormality". Metab. Clin. Exp. 30 (5): 502–9. doi:10.1016/0026-0495(81)90188-8. PMID 6785551.
- ^ Zhu X, Wu G, Zeng W, Xue H, Chen B (2005). "Cysteine mutants of human apolipoprotein A-I: a study of secondary structural and functional properties". J. Lipid Res. 46 (6): 1303–11. doi:10.1194/jlr.M400401-JLR200. PMID 15805548.
- ^ Chiesa G, Sirtori CR (2003). "Apolipoprotein A-I(Milano): current perspectives". Curr. Opin. Lipidol. 14 (2): 159–63. doi:10.1097/00041433-200304000-00007. PMID 12642784.
- ^ a b "Apo A-I-Milano Trial: Where are we now?". Cleveland Clinic. Retrieved 2008-07-26.
- ^ Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M et al. (November 2003). "Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial". JAMA 290 (17): 2292–300. doi:10.1001/jama.290.17.2292. PMID 14600188.
- ^ "Apo A-I Milano". Cedars-Sinai Heart Institute. Retrieved 2008-07-26. [dead link]
- ^ Singh P, Singh M, Kaur TP, Grewal SS (September 2007). "A novel haplotype in ApoAI-CIII-AIV gene region is detrimental to Northwest Indians with coronary heart disease". Int. J. Cardiol. 130 (3): e93–5. doi:10.1016/j.ijcard.2007.07.029. PMID 17825930.
- ^ Singh P, Singh M, Gaur S, Kaur T (June 2007). "The ApoAI-CIII-AIV gene cluster and its relation to lipid levels in type 2 diabetes mellitus and coronary heart disease: determination of a novel susceptible haplotype". Diab Vasc Dis Res 4 (2): 124–9. doi:10.3132/dvdr.2007.030. PMID 17654446.
- ^ Vollbach H, Heun R, Morris CM, Edwardson JA, McKeith IG, Jessen F et al. (2005). "APOA1 polymorphism influences risk for early-onset non-familial AD". Ann. Neurol. 58 (3): 436–41. doi:10.1002/ana.20593. PMID 16130094.
- ^ Maezawa I, Jin LW, Woltjer RL, Maeda N, Martin GM, Montine TJ et al. (2004). "Apolipoprotein E isoforms and apolipoprotein A-I protect from amyloid precursor protein carboxy terminal fragment-associated cytotoxicity". J. Neurochem. 91 (6): 1312–21. doi:10.1111/j.1471-4159.2004.02818.x. PMID 15584908.
- ^ Solomon A, Murphy CL, Kestler D, Coriu D, Weiss DT, Makovitzky J et al. (2006). "Amyloid contained in the knee joint meniscus is formed from apolipoprotein A-I". Arthritis Rheum. 54 (11): 3545–50. doi:10.1002/art.22201. PMID 17075859.
- ^ Ma J, Liao XL, Lou B, Wu MP (2004). "Role of apolipoprotein A-I in protecting against endotoxin toxicity". Acta Biochim. Biophys. Sin. (Shanghai) 36 (6): 419–24. doi:10.1093/abbs/36.6.419. PMID 15188057.
- ^ Huang JT, Wang L, Prabakaran S, Wengenroth M, Lockstone HE, Koethe D et al. (2007). "Independent protein-profiling studies show a decrease in apolipoprotein A1 levels in schizophrenia CSF, brain and peripheral tissues". Mol Psychiatry 13 (12): 1118–28. doi:10.1038/sj.mp.4002108. PMID 17938634.
- ^ Singh P, Singh M, Kaur T (2008). "Role of apolipoproteins E and A-I: Epistatic villains of triglyceride mediation in coronary heart disease". Int J Cardiol (Epub Ahead) 134 (3): 410–2. doi:10.1016/j.ijcard.2007.12.102. PMID 18378026.
- ^ Wehmeier K, Beers A, Haas MJ, Wong NC, Steinmeyer A, Zugel U et al. (2005). "Inhibition of apolipoprotein AI gene expression by 1, 25-dihydroxyvitamin D3". Biochim. Biophys. Acta 1737 (1): 16–26. doi:10.1016/j.bbalip.2005.09.004. PMID 16236546.
- ^ Lahoz C, Peña R, Mostaza JM, Jiménez J, Subirats E, Pintó X et al. (2003). "Apo A-I promoter polymorphism influences basal HDL-cholesterol and its response to pravastatin therapy". Atherosclerosis 168 (2): 289–95. doi:10.1016/S0021-9150(03)00094-7. PMID 12801612.
- ^ Fitzgerald ML, Morris AL, Rhee JS, Andersson LP, Mendez AJ, Freeman MW (September 2002). "Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I". J. Biol. Chem. 277 (36): 33178–87. doi:10.1074/jbc.M204996200. PMID 12084722.
- ^ Deeg MA, Bierman EL, Cheung MC (March 2001). "GPI-specific phospholipase D associates with an apoA-I- and apoA-IV-containing complex". J. Lipid Res. 42 (3): 442–51. PMID 11254757.
- ^ Pussinen PJ, Jauhiainen M, Metso J, Pyle LE, Marcel YL, Fidge NH et al. (January 1998). "Binding of phospholipid transfer protein (PLTP) to apolipoproteins A-I and A-II: location of a PLTP binding domain in the amino terminal region of apoA-I". J. Lipid Res. 39 (1): 152–61. PMID 9469594.
- ^ "STRING: Known and Predicted Protein-Protein Interactions".
External links
- Apolipoprotein A-I at the US National Library of Medicine Medical Subject Headings (MeSH)
- Applied Research on Apolipoprotein-A1
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Lipids: lipoprotein particle metabolism
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| Lipoprotein particle classes and subclasses |
- delivery of TGs: Chylomicron
- VLDL
- delivery of C and CE: IDL
- LDL
- lb LDL
- sd LDL
- Lp(a)
- HDL
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| Apolipoproteins |
- APOA
- APOB
- APOC
- APOD
- APOE
- APOH
- SAA
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| Extracellular enzymes |
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| Lipid transfer proteins |
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| Cell surface receptors |
- IDL: LRP
- LRP1
- LRP1B
- LRP2
- LRP3
- LRP4
- LRP5
- LRP5L
- LRP6
- LRP8
- LRP10
- LRP11
- LRP12
- LDL: LDLR
- LRPAP1
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| ATP-binding cassette transporter |
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Index of inborn errors of metabolism
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| Description |
- Metabolism
- Enzymes and pathways: citric acid cycle
- pentose phosphate
- glycoproteins
- glycosaminoglycans
- phospholipid
- cholesterol and steroid
- sphingolipids
- eicosanoids
- amino acid
- urea cycle
- nucleotide
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| Disorders |
- Citric acid cycle and electron transport chain
- Glycoprotein
- Proteoglycan
- Fatty-acid
- Phospholipid
- Cholesterol and steroid
- Eicosanoid
- Amino acid
- Purine-pyrimidine
- Heme metabolism
- Symptoms and signs
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| Treatment |
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