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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
来源:
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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