BioSpace Collaborative

Academic/Biomedical Research
News & Jobs
Biotechnology and Pharmaceutical Channel Medical Device and Diagnostics Channel Clinical Research Channel BioSpace Collaborative    Job Seekers:  Register | Login          Employers:  Register | Login  

NEWSLETTERS
Free Newsletters
Archive
My Subscriptions

NEWS
News by Subject
News by Disease
News by Date
PLoS
Search News
Post Your News
JoVE

CAREER NETWORK
Job Seeker Login
Most Recent Jobs
Search Jobs
Post Resume
Career Fairs
Career Resources
For Employers

HOTBEDS
Regional News
US & Canada
  Biotech Bay
  Biotech Beach
  Genetown
  Pharm Country
  BioCapital
  BioMidwest
  Bio NC
  BioForest
  Southern Pharm
  BioCanada East
  C2C Services & Suppliers™
Europe
Asia

DIVERSITY

PROFILES
Company Profiles

INTELLIGENCE
Research Store

INDUSTRY EVENTS
Research Events
Post an Event
RESOURCES
Real Estate
Business Opportunities

PLoS By Category | Recent PLoS Articles
Chemistry - Hematology - Immunology

Modeling and Molecular Dynamics of HPA-1a and -1b Polymorphisms: Effects on the Structure of the ß3 Subunit of the aIIbß3 Integrin
Published: Wednesday, November 14, 2012
Author: Vincent Jallu et al.

by Vincent Jallu, Pierre Poulain, Patrick F. J. Fuchs, Cecile Kaplan, Alexandre G. de Brevern

Background

The HPA-1 alloimmune system carried by the platelet integrin aIIbß3 is the primary cause of alloimmune thrombocytopenia in Caucasians and the HPA-1b allele might be a risk factor for thrombosis. HPA-1a and -1b alleles are defined by a leucine and a proline, respectively, at position 33 in the ß3 subunit. Although the structure of aIIbß3 is available, little is known about structural effects of the L33P substitution and its consequences on immune response and integrin functions.

Methodology/Principal Findings

A complete 3D model of the L33-ß3 extracellular domain was built and a P33 model was obtained by in silico mutagenesis. We then performed molecular dynamics simulations. Analyses focused on the PSI, I-EGF-1, and I-EGF-2 domains and confirmed higher exposure of residue 33 in the L33 ß3 form. These analyses also showed major structural flexibility of all three domains in both forms, but increased flexibility in the P33 ß3 form. The L33P substitution does not alter the local structure (residues 33 to 35) of the PSI domain, but modifies the structural equilibrium of the three domains.

Conclusions

These results provide a better understanding of HPA-1 epitopes complexity and alloimmunization prevalence of HPA-1a. P33 gain of structure flexibility in the ß3 knee may explain the increased adhesion capacity of HPA-1b platelets and the associated thrombotic risk. Our study provides important new insights into the relationship between HPA-1 variants and ß3 structure that suggest possible effects on the alloimmune response and platelet function.

  More...