The inside-out signaling has been most clearly demonstrated for the platelet integrin alphaIIbbeta3: in unstimulated platelets, alphaIIbbeta3 exists in a """"""""latent"""""""" noncompetent state - it does not bind its abundant blood-borne ligands such as fibrinogen, whereas upon stimulation with agonists, such as thrombin and ADP, alphaIIbbeta3 undergoes a conformational change and is subsequently activated to a high-affinity ligand binding state. This conformational change is thought to occur first in the cytoplasmic domain of alphaIIbbeta3, which then propagates through the transmembrane region to the extracellular domain resulting in high affinity ligand binding. The molecular details of the conformational transition for alphaIIbbeta3 cytoplasmic domain from its """"""""closed inactive form"""""""" to the """"""""open active state"""""""" remains poorly understood. It was recently shown that when inactive, the cytoplasmic tails of alphaIIbbeta3 interact with each other and with a divalent cation to form a ternary cytoplasmic domain complex. On the other hand, selective mutations on alphaIIb and/or beta3 tails result in constitutively active receptor, which suggests that the cytoplasmic domains of these active mutants adopt different conformation from the wild type. Thus the overall objective of this proposal is to gain insights into the conformation induced integrin signaling by determining structures of alphaIIbbeta3 cytoplasmic domain and its """"""""active"""""""" mutants.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL010259-03
Application #
6388741
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Mondoro, Traci
Project Start
2001-07-01
Project End
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$41,996
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Sengupta, Dibyendu; Kahn, Andrew M; Burns, Jane C et al. (2012) Image-based modeling of hemodynamics in coronary artery aneurysms caused by Kawasaki disease. Biomech Model Mechanobiol 11:915-32