Document Detail


The linker between the D3 and A1 domains of vWF suppresses A1-GPIbα catch bonds by site-specific binding to the A1 domain.
MedLine Citation:
PMID:  23775931     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Platelet attachment to von Willebrand factor (vWF) requires the interaction between the platelet GP1bα and exposed vWF-A1 domains. Structural insights into the mechanism of the A1-GP1bα interaction have been limited to an N-terminally truncated A1 domain that lacks residues Q1238  - E1260 that make up the linker between the D3 and A1 domains of vWF. We have demonstrated that removal of these residues destabilizes quaternary interactions in the A1A2A3 tridomain and contributes to platelet activation under high shear (Auton et al., J Biol Chem 2012;287:14579-14585). In this study, we demonstrate that removal of these residues from the single A1 domain enhances platelet pause times on immobilized A1 under rheological shear. A rigorous comparison between the truncated A1-1261 and full length A1-1238 domains demonstrates a kinetic stabilization of the A1 domain induced by these N-terminal residues as evident in the enthalpy of the unfolding transition. This stabilization occurs through site and sequence-specific binding of the N-terminal peptide to A1. Binding of free N-terminal peptide to A1-1261 has an affinity KD=46±6μM and this binding although free to dissociate is sufficient to suppress the platelet pause times to levels comparable to A1-1238 under shear stress. Our results support a dual-structure/function role for this linker region involving a conformational equilibria that maintains quaternary A domain associations in the inactive state of vWF at low shear and an intra-A1-domain conformation that regulates the strength of platelet GP1bα-vWF A1 domain associations in the active state of vWF at high shear.
Authors:
Alexander Tischer; Miguel A Cruz; Matthew Auton
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Protein science : a publication of the Protein Society     Volume:  22     ISSN:  1469-896X     ISO Abbreviation:  Protein Sci.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-07-29     Completed Date:  2014-02-07     Revised Date:  2014-08-03    
Medline Journal Info:
Nlm Unique ID:  9211750     Medline TA:  Protein Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1049-59     Citation Subset:  IM    
Copyright Information:
© 2013 The Protein Society.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Binding Sites*
Blood Platelets / metabolism
Humans
Membrane Glycoproteins / chemistry*,  metabolism
Molecular Sequence Data
Protein Binding
Protein Folding
Protein Structure, Quaternary
Protein Structure, Tertiary
Recombinant Proteins / chemistry,  metabolism
von Willebrand Factor / chemistry*,  metabolism*
Grant Support
ID/Acronym/Agency:
HL109109/HL/NHLBI NIH HHS; R01 HL109109/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Membrane Glycoproteins; 0/Recombinant Proteins; 0/adhesion receptor; 0/von Willebrand Factor
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Specific airway resistance in children: Panting or tidal breathing?
Next Document:  Retinal nerve fiber layer thickness and visual hallucinations in Parkinson's Disease.