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Published on: March 8, 2017
Integrin alphaIIbbeta3:ligand interactions are linked to binding-site remodeling
Roy R Hantgan1, Mary C Stahle, John H Connor
1Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1019, USA. rhantgan@wfubmc.edu
Protein Science : a Publication of the Protein Society
|August 1, 2006
Summary
High-affinity binding to alphaIIbbeta3 integrin involves receptor remodeling. Echistatin binding perturbs resting integrin conformation, while fibrinogen requires priming for activation.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- The alphaIIbbeta3 integrin plays a crucial role in platelet aggregation and thrombosis.
- Understanding integrin-ligand interactions is key to developing anti-thrombotic therapies.
Purpose of the Study:
- To investigate the relationship between high-affinity ligand binding and conformational changes in the alphaIIbbeta3 integrin.
- To differentiate between 'priming' and 'regulated' ligands based on their interaction mechanisms.
Main Methods:
- Sedimentation velocity, fluorescence anisotropy, and solid-phase binding assays were used to study ligand-integrin interactions.
- Molecular graphics modeling was employed to analyze binding interactions.
- Site-directed mutagenesis of echistatin variants was performed to probe specific residue contributions.
Main Results:
- Electrostatic interactions at the alphaIIb/beta3 interface, particularly involving Aspartate 26, are critical for perturbing the resting integrin conformation.
- Echistatin binding can directly induce conformational changes, while fibrinogen's gamma-module requires a 'priming' step involving ectodomain changes.
- The C-terminal region of fibrinogen's gamma-module is not essential for alphaIIbbeta3 integrin binding.
Conclusions:
- High-affinity ligand binding to alphaIIbbeta3 integrin is coupled to binding-site remodeling and conformational shifts.
- Ligands can be classified as 'priming' (binding to resting receptor) or 'regulated' (requiring remodeling first), influencing their interaction dynamics.
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