| N-terminal flanking region of A1 domain in von Willebrand factor stabilizes structure of A1A2A3 complex and modulates platelet activation under shear stress. | |
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MedLine Citation:
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PMID: 22431729 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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von Willebrand factor (vWF) mediates platelet adhesion and thrombus formation via its interaction with the platelet receptor glycoprotein (GP)Ibα. We have analyzed two A1A2A3 tri-domain proteins to demonstrate that the amino acid sequence, Gln(1238)-Glu(1260), in the N-terminal flanking region of the A1 domain, together with the association between the A domains, modulates vWF-GPIbα binding and platelet activation under shear stress. Using circular dichroism spectroscopy and differential scanning calorimetry, we have described that sequence Gln(1238)-Glu(1260) stabilizes the structural conformation of the A1A2A3 tri-domain complex. The structural stabilization imparted by this particular region inhibits the binding capacity of the tri-domain protein for GPIbα. Deletion of this region causes a conformational change in the A1 domain that increases binding to GPIbα. Only the truncated protein was capable of effectively blocking ristocetin-induced platelet agglutination. To determine the capacity of activating platelets via the interaction with GPIbα, whole blood was incubated with the N-terminal region truncated or intact tri-A domain protein prior to perfusion over a fibrin(ogen)-coated surface. At a high shear rate of 1,500 s(-1), platelets from blood containing the truncated protein rapidly bound, covering >90% of the fibrin(ogen) surface area, whereas the intact tri-A domain protein induced platelets to bind <10%. The results obtained in this study ascertain the relevant role of the structural association between the N-terminal flanking region of the A1 domain (amino acids Gln(1238)-Glu(1260)) and the A1A2A3 domain complex in preventing vWF to bind spontaneously to GPIbα in solution under high shear forces. |
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Authors:
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Matthew Auton; Katie E Sowa; Molly Behymer; Miguel A Cruz |
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Publication Detail:
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Type: Clinical Trial; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-03-19 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-04-30 Completed Date: 2012-07-02 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 14579-85 Citation Subset: IM |
Affiliation:
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Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Anti-Bacterial Agents
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pharmacology Female Fibrinogen / genetics, metabolism Humans Male Membrane Glycoproteins / genetics, metabolism* Multiprotein Complexes / genetics, metabolism Platelet Activation / drug effects, physiology* Protein Structure, Quaternary Protein Structure, Tertiary Ristocetin / pharmacology Stress, Physiological / drug effects, physiology* von Willebrand Factor / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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HL109109/HL/NHLBI NIH HHS; HL72886/HL/NHLBI NIH HHS; R01 HL109109/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anti-Bacterial Agents; 0/Membrane Glycoproteins; 0/Multiprotein Complexes; 0/adhesion receptor; 0/von Willebrand Factor; 1404-55-3/Ristocetin; 9001-32-5/Fibrinogen |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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