Gain of von Willebrand factor-binding function by mutagenesis of a species-conserved residue within the leucine-rich repeat region of platelet glycoprotein Ibalpha.

Abstract:

:Glycoprotein (GP) Ibalpha, a member of the leucine-rich repeat (LRR) protein family, mediates platelet adhesion to immobilized von Willebrand factor (VWF). We investigated the role in VWF binding of charged residues in the LRR region of GP Ibalpha that are conserved in human, canine, and murine proteins. Substitution of His86 with either Ala or Glu resulted in a gain of VWF-binding function as judged by increased VWF binding in the presence of the modulators ristocetin and botrocetin and by enhanced adhesion of Chinese hamster ovary (CHO) cells expressing the mutant GP Ibalpha to immobilized VWF under conditions of flow. This is the first report of a gain-of-function phenotype resulting from mutations in the LRR region of GP Ibalpha. Because His86 is 2 nm away from the region of GP Ibalpha with the largest surface of contact with VWF, the data suggest that the LRRs regulate GP Ibalpha affinity for VWF allosterically.

journal_name

Blood

journal_title

Blood

authors

Peng Y,Shrimpton CN,Dong JF,López JA

doi

10.1182/blood-2005-02-0514

subject

Has Abstract

pub_date

2005-09-15 00:00:00

pages

1982-7

issue

6

eissn

0006-4971

issn

1528-0020

pii

2005-02-0514

journal_volume

106

pub_type

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