Molecular dynamics simulation of human LOX-1 provides an explanation for the lack of OxLDL binding to the Trp150Ala mutant.
BACKGROUND
Dimeric lectin-like oxidized low-density lipoprotein receptor-1 LOX-1 is the target receptor for oxidized low density lipoprotein in endothelial cells. In vivo assays revealed that in LOX-1 the basic spine arginine residues are important for binding, which is lost upon mutation of Trp150 with alanine. Molecular dynamics simulations of the wild-type LOX-1 and of the Trp150Ala mutant C-type lectin-like domains, have been carried out to gain insight into the severe inactivating effect.


RESULTS
The mutation does not alter the dimer stability, but a different dynamical behaviour differentiates the two proteins. As described by the residues fluctuation, the dynamic cross correlation map and the principal component analysis in the wild-type the two monomers display a symmetrical motion that is not observed in the mutant.


CONCLUSIONS
The symmetrical motion of monomers is completely damped by the structural rearrangement caused by the Trp150Ala mutation. An improper dynamical coupling of the monomers and different fluctuations of the basic spine residues are observed, with a consequent altered binding affinity.
Falconi
Mattia
M
Department of Biology and Center of Biostatistics and Bioinformatics, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome, Italy, 00133. falconi@uniroma2.it
Biocca
Silvia
S
Novelli
Giuseppe
G
Desideri
Alessandro
A
D000409:Alanine / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014364:Tryptophan / Q000235:genetics / Q000378:metabolism
D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D021122:Protein Subunits; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D014364:Tryptophan; D000409:Alanine