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

Silvia Biocca, Mattia Falconi, Ilaria Filesi, Francesco Baldini, Lucia Vecchione, Ruggiero Mango, Francesco Romeo, Giorgio Federici, Alessandro Desideri, Giuseppe Novelli

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish
Article numbere4648
JournalPLoS One
Volume4
Issue number2
DOIs
Publication statusPublished - Feb 27 2009

Fingerprint

Functional analysis
oxen
molecular dynamics
Molecular Dynamics Simulation
Polymorphism
Molecular dynamics
genetic polymorphism
receptors
Computer simulation
Static Electricity
spine (bones)
Electrostatics
low density lipoprotein
mitogen-activated protein kinase
Macrophages
macrophages
Spine
mutation
Scavenger Receptors
Mutation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Biocca, S., Falconi, M., Filesi, I., Baldini, F., Vecchione, L., Mango, R., ... Novelli, G. (2009). Functional analysis and molecular dynamics simulation of LOX-1 K167N polymorphism reveal alteration of receptor activity. PLoS One, 4(2), [e4648]. https://doi.org/10.1371/journal.pone.0004648

Functional analysis and molecular dynamics simulation of LOX-1 K167N polymorphism reveal alteration of receptor activity. / Biocca, Silvia; Falconi, Mattia; Filesi, Ilaria; Baldini, Francesco; Vecchione, Lucia; Mango, Ruggiero; Romeo, Francesco; Federici, Giorgio; Desideri, Alessandro; Novelli, Giuseppe.

In: PLoS One, Vol. 4, No. 2, e4648, 27.02.2009.

Research output: Contribution to journalArticle

Biocca, S, Falconi, M, Filesi, I, Baldini, F, Vecchione, L, Mango, R, Romeo, F, Federici, G, Desideri, A & Novelli, G 2009, 'Functional analysis and molecular dynamics simulation of LOX-1 K167N polymorphism reveal alteration of receptor activity', PLoS One, vol. 4, no. 2, e4648. https://doi.org/10.1371/journal.pone.0004648
Biocca, Silvia ; Falconi, Mattia ; Filesi, Ilaria ; Baldini, Francesco ; Vecchione, Lucia ; Mango, Ruggiero ; Romeo, Francesco ; Federici, Giorgio ; Desideri, Alessandro ; Novelli, Giuseppe. / Functional analysis and molecular dynamics simulation of LOX-1 K167N polymorphism reveal alteration of receptor activity. In: PLoS One. 2009 ; Vol. 4, No. 2.
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