Functional analysis and molecular dynamics simulation of LOX-1 K167N polymorphism reveal alteration of receptor activity

Biocca, S., Falconi, M., Filesi, I., Baldini, F., Vecchione, L., Mango, R., Romeo, F., Federici, G., Desideri, A. and Novelli, G. (2009) Functional analysis and molecular dynamics simulation of LOX-1 K167N polymorphism reveal alteration of receptor activity. PLoS ONE, 4(2), e4648. (doi:10.1371/journal.pone.0004648) (PMID:19247493) (PMCID:PMC2645694)

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Abstract

The human lectin-like oxidized low density lipoprotein receptor 1 LOX-1, encoded by the ORL1 gene, is the major scavenger receptor for oxidized low density lipoprotein in endothelial cells. Here we report on the functional effects of a coding SNP, c.501G>C, which produces a single amino acid change (K>N at codon 167). Our study was aimed at elucidating whether the c.501G>C polymorphism changes the binding affinity of LOX-1 receptor altering its function. The presence of p.K167N mutation reduces ox-LDL binding and uptake. Ox-LDL activated extracellular signal-regulated kinases 1 and 2 (ERK 1/2) is inhibited. Furthermore, ox-LDL induced biosynthesis of LOX-1 receptors is dependent on the p.K167N variation. In human macrophages, derived from c.501G>C heterozygous individuals, the ox-LDL induced LOX-1 46 kDa band is markedly lower than in induced macrophages derived from c.501G>C controls. Investigation of p.K167N mutation through molecular dynamics simulation and electrostatic analysis suggests that the ox-LDL binding may be attributed to the coupling between the electrostatic potential distribution and the asymmetric flexibility of the basic spine residues. The N/N-LOX-1 mutant has either interrupted electrostatic potential and asymmetric fluctuations of the basic spine arginines.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baldini, Dr Francesco
Authors: Biocca, S., Falconi, M., Filesi, I., Baldini, F., Vecchione, L., Mango, R., Romeo, F., Federici, G., Desideri, A., and Novelli, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Copyright Holders:Copyright © 2009 The Authors
First Published:First published in PLoS ONE 4(2):e4648
Publisher Policy:Reproduced under a Creative Commons License

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