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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