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Molecular dynamics simulation of human LOX-1 provides an explanation for the lack of OxLDL binding to the Trp150Ala mutant.

Falconi M, Biocca S, Novelli G, Desideri A - BMC Struct. Biol. (2007)

Bottom Line: 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.The symmetrical motion of monomers is completely damped by the structural rearrangement caused by the Trp150Ala mutation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology and Center of Biostatistics and Bioinformatics, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome, Italy, 00133. falconi@uniroma2.it

ABSTRACT

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.

Conclusion: 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.

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RMSD from starting structures of LOX-1 CTLD wild-type (black line) and Trp150Ala (grey line) proteins. The grey box indicates the trajectory fraction that has not been used in the analysis.
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Figure 2: RMSD from starting structures of LOX-1 CTLD wild-type (black line) and Trp150Ala (grey line) proteins. The grey box indicates the trajectory fraction that has not been used in the analysis.

Mentions: The main chain root mean square deviations (RMSDs) were calculated, for the trajectories of the two proteins, from the starting structures as a function of time (Fig. 2). Although the RMSDs reach a stable value within the first nanosecond all the analyses have been carried out discarding the first three nanoseconds, i.e. over the last seven nanoseconds. This was done to guarantee an investigation over a well thermalized system. Time evolution of the number of residues in α-helix, β-strand and random coil secondary structures, gyration radius, total solvent accessible surface area (additional file 1) and RMSD (Fig. 1), all confirm the protein stability over the entire trajectory chosen for the analysis.


Molecular dynamics simulation of human LOX-1 provides an explanation for the lack of OxLDL binding to the Trp150Ala mutant.

Falconi M, Biocca S, Novelli G, Desideri A - BMC Struct. Biol. (2007)

RMSD from starting structures of LOX-1 CTLD wild-type (black line) and Trp150Ala (grey line) proteins. The grey box indicates the trajectory fraction that has not been used in the analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2194713&req=5

Figure 2: RMSD from starting structures of LOX-1 CTLD wild-type (black line) and Trp150Ala (grey line) proteins. The grey box indicates the trajectory fraction that has not been used in the analysis.
Mentions: The main chain root mean square deviations (RMSDs) were calculated, for the trajectories of the two proteins, from the starting structures as a function of time (Fig. 2). Although the RMSDs reach a stable value within the first nanosecond all the analyses have been carried out discarding the first three nanoseconds, i.e. over the last seven nanoseconds. This was done to guarantee an investigation over a well thermalized system. Time evolution of the number of residues in α-helix, β-strand and random coil secondary structures, gyration radius, total solvent accessible surface area (additional file 1) and RMSD (Fig. 1), all confirm the protein stability over the entire trajectory chosen for the analysis.

Bottom Line: 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.The symmetrical motion of monomers is completely damped by the structural rearrangement caused by the Trp150Ala mutation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology and Center of Biostatistics and Bioinformatics, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome, Italy, 00133. falconi@uniroma2.it

ABSTRACT

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus