Functional Analysis and Molecular Dynamics Simulation of LOX-1 K167N Polymorphism Reveal Alteration of Receptor Activity

被引:52
作者
Biocca, Silvia [1 ,3 ]
Falconi, Mattia [2 ,3 ]
Filesi, Ilaria [1 ]
Baldini, Francesco [1 ]
Vecchione, Lucia [4 ,5 ]
Mango, Ruggiero [6 ,7 ]
Romeo, Francesco [6 ,8 ,9 ]
Federici, Giorgio [6 ]
Desideri, Alessandro [2 ,3 ]
Novelli, Giuseppe [3 ,4 ,5 ,8 ,9 ]
机构
[1] Univ Roma Tor Vergata, Dept Neurosci, Rome, Italy
[2] Univ Roma Tor Vergata, Dept Biol, I-00173 Rome, Italy
[3] Univ Roma Tor Vergata, Ctr Biostat & Bioinformat, Rome, Italy
[4] Univ Roma Tor Vergata, Dept Biopathol & Diagnost Imaging, Rome, Italy
[5] Univ Roma Tor Vergata, Sch Med, Ctr Excellence Genom Risk Assessment Multifactor, Rome, Italy
[6] Univ Roma Tor Vergata, Dept Internal Med, Rome, Italy
[7] IRCCS Humanitas, Milan, Italy
[8] Univ Arkansas Med Sci, Dept Internal Med, Little Rock, AR USA
[9] Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA
关键词
D O I
10.1371/journal.pone.0004648
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:12
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