Efflux and Atherosclerosis

Singaraja, Roshni R.; Brunham, Liam R.; Visscher, Henk; Kastelein, John J.P.; Hayden, Michael R.

doi:10.1161/01.atv.0000078520.89539.77

Cited by 229 publications

(116 citation statements)

References 90 publications

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“…The accumulated literature supports the existence of functionally different alleles of ABCA1 that affect both discrete disease states (Singaraja et al 2003) and quantitative traits (Wang et al 2000;Clee et al 2001;FrikkeSchmidt et al 2004). One of the principal problems has been that the sample sizes of most studies have been small, typically entailing less than 1,000 individuals.…”

Section: Introductionmentioning

confidence: 89%

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Katzov

Bennet

Höglund³

et al. 2005

J Hum Genet

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The ATP-binding cassette transporter A1 encoded by ABCA1 plays an integral role in the efflux of cellular cholesterol and phospholipids, but may also be a central mediator of b-amyloid (Ab) processing. Here, genetic association of the common R219K variant of ABCA1 is shown with cerebrospinal fluid (CSF) Ab 1-42 levels, reinforcing emerging evidence of a connection between lipid and Ab metabolism. In support of this finding we demonstrate for the first time that CSF cholesterol and Ab 1-42 are correlated. To affirm the plausible impact of ABCA1 variation on cholesterol and related traits as well as to empower a survey of possible interactions (e.g. age, gender, and smoking), a large Swedish population consisting of over 2,700 individuals was enlisted and extensive measures of plasma lipid parameters carried out. These analyses revealed that R219K has a strong effect on apolipoprotein B (APOB) and LDLcholesterol (LDL-C) among smokers (P=0.000055 and P=0.00059, respectively), but not among non-smokers. In contrast, no effect was evident with apolipoprotein A (APOA1) or HDL-cholesterol (HDL-C) levels. Plasma APOB and LDL-C, but not APOA1 and HDL-C, were shown to be markedly elevated in smokers versus nonsmokers, affirming that smoking may selectively impact the former pathway. No other genetic markers in ABCA1 exhibit effects as large as R219K, although a modest independent effect of R1587K was observed. Our data illuminate a possible genetic link between Ab and cholesterol metabolism, but also provide an intriguing example of an environmental exposure that may modify a genotype-phenotype relationship.

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Section: Introductionmentioning

confidence: 89%

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Katzov

Bennet

Höglund³

et al. 2005

J Hum Genet

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“…More than 70 mutations have been identified in the ABCA1 gene. Indeed, mutations in ABCA1 lead to Tangier disease, which is characterized by plasma HDL deficiency (6)(7)(8)(9)(10). ABCA1 has two large extracellular domains (ECDs), and the two intramolecular disulfide bonds between them are necessary for apoA-I binding and HDL formation (11)(12)(13) (Fig.…”

mentioning

confidence: 99%

ABCA1 dimer–monomer interconversion during HDL generation revealed by single-molecule imaging

Nagata

Nakada

Kasai

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The generation of high-density lipoprotein (HDL), one of the most critical events for preventing atherosclerosis, is mediated by ATPbinding cassette protein A1 (ABCA1). ABCA1 is known to transfer cellular cholesterol and phospholipids to apolipoprotein A-I (apoA-I) for generating discoidal HDL (dHDL) particles, composed of 100-200 lipid molecules surrounded by two apoA-I molecules; however, the regulatory mechanisms are still poorly understood. Here we observed ABCA1-GFP and apoA-I at the level of single molecules on the plasma membrane via a total internal reflection fluorescence microscope. We found that about 70% of total ABCA1-GFP spots are immobilized on the plasma membrane and estimated that about 89% of immobile ABCA1 molecules are in dimers. Furthermore, an ATPase-deficient ABCA1 mutant failed to be immobilized or form a dimer. We found that the lipid acceptor apoA-I interacts with the ABCA1 dimer to generate dHDL and is followed by ABCA1 dimermonomer interconversion. This indicates that the formation of the ABCA1 dimer is the key for apoA-I binding and nascent HDL generation. Our findings suggest the physiological significance of conversion of the ABCA1 monomer to a dimer: The dimer serves as a receptor for two apoA-I molecules for dHDL particle generation.membrane protein | transporter P lasma high-density lipoprotein (HDL) is critical for preventing coronary artery disease (1). A member of the ATPdependent transporter family of ABC proteins, ATP-binding cassette protein A1 (ABCA1) initiates the generation of discoidal HDL (dHDL), a bilayer fragment consisting of 100-200 lipids wrapped by two molecules of apolipoprotein A-I (apoA-I) (2-4), by exporting cholesterol and phospholipids to lipid-free apoA-I in serum (5). More than 70 mutations have been identified in the ABCA1 gene. Indeed, mutations in ABCA1 lead to Tangier disease, which is characterized by plasma HDL deficiency (6-10). ABCA1 has two large extracellular domains (ECDs), and the two intramolecular disulfide bonds between them are necessary for apoA-I binding and HDL formation (11-13) (Fig. 1A). Two pieces of evidence suggest that apoA-I interacts with a specific conformation of the ECDs in an ATP-dependent manner: Chemical cross-linkers can cross-link apoA-I with ABCA1, and ATPasedeficient ABCA1 mutants fail to mediate apoA-I binding and crosslinking. However, the importance of direct binding of ABCA1-apoA-I in HDL formation is still controversial and, furthermore, how a dHDL particle containing two molecules of apoA-I is formed from lipid-free apoA-I monomers and membrane lipids is unknown.To address these issues, we performed single-molecule fluorescence imaging (14, 15) of ABCA1 and apoA-I on the plasma membrane (PM) via a total internal reflection fluorescence (TIRF) microscope in living cells. We examined the dynamic behaviors of ABCA1 as well as the interaction of ABCA1 with apoA-I, and found that ABCA1 forms an immobile dimer on the PM; the ABCA1 dimer then dissociates into diffusing monomers upon interaction with apoA-I, finally gen...

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“…As it is difficult to choose and study the SNPs which are more likely to contribute in disease development hence in this condition in silico approach is a convenient way to distinguish the damaging SNPs using specific algorithms that can discriminate between neutral and deleterious SNPs [48].Hence an effort was made to identify SNPs that can modify the structure, function and expression of the PCNA gene. As most of the disease associated SNPs are found in the exons or coding regions, also known as non-synonymous SNPs [49,50] have submitted the 42 nsSNPs of PCNA to various in silico SNP characterizing tools and out of these 42 nsSNPs, 5 nsSNPs (Q38R, S39R, E104G, L182W and K248N) were found to be damaging.…”

Section: Discussionmentioning

confidence: 99%

Untitled

2017

RJLBPCS

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Aim: Proliferating cell nuclear antigen (PCNA) is an ancillary protein that assists in DNA replication and DNA repair process. Detection of mutations in PCNA gene or protein could be helpful to analyze many disorders relating to DNA replication and repair. In the present study, non-synonymous single nucleotide polymorphisms (nsSNPs) generated by missense mutation were studied using different computational methods to evaluate the nsSNPs that may be deleterious to PCNA function.Method: The missense nsSNPs were retrieved from the database of NCBI and subjected to functional prediction by the computational algorithms. The evolutionary conservation data of the PCNA protein was obtained from the ConSurf web server. The protein structural analysis for the variants was performed using I-Mutant, SPDB viewer and YASARA to check their structural variations and energy minimizations. Results: Out of the 42 nsSNPs, 5 nsSNPs namely rs780735449 (Q38R), rs1050525 (S39R), rs781573975 (E104G), rs772308650 (L182W) and rs753494859 (K248N) were identified as deleterious by using different computational algorithms. The evolutionary conservation data revealed that all the high risk nsSNPs positions were highly conserved and were either functional or structural residues in the protein. The I-Mutant tool had showed a decrease in the protein stability for the five high risk nsSNPs. A deviance in the energy minimization was observed for the variants with respect to the native protein. The RMSD (root mean square deviation) and TM (template modeling) values predicted that the mutants were structurally similar to the wild type protein. The PTM (post translational modifications) analysis using various in silico tools showed that S39R and K248N were putative PTM sites and through FTSite it was observed that these two variants were also involved in the ligand binding sites.Conclusion: Through the robust use of various in silico tools, five nsSNPs of PCNA protein were found to deleterious. Out of them two mutations at 39th and 248th positions (S39R & K248N) are to be further validated for their effect on the PCNA protein function.

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Efflux and Atherosclerosis

Cited by 229 publications

References 90 publications

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

ABCA1 dimer–monomer interconversion during HDL generation revealed by single-molecule imaging

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