Functional analysis and molecular dynamics simulation of LOX-1 K167N polymorphism reveal alteration of receptor activity.
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.
Biocca
Silvia
S
Department of Neuroscience, University of Tor Vergata, Rome, Italy. biocca@med.uniroma2.it
Falconi
Mattia
M
Filesi
Ilaria
I
Baldini
Francesco
F
Vecchione
Lucia
L
Mango
Ruggiero
R
Romeo
Francesco
F
Federici
Giorgio
G
Desideri
Alessandro
A
Novelli
Giuseppe
G
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003062:Codon; D006579:Heterozygote; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D051127:Scavenger Receptors, Class E / Q000235:genetics* / Q000378:metabolism; D055672:Static Electricity
D003062:Codon; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3