The proof is in the crystal

López, José A.; Munday, Adam D.

doi:10.1182/blood-2009-09-242834

Cited by 2 publications

(1 citation statement)

References 6 publications

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“…These structural units are configured in a curved shape with a parallel β-sheet on the concave side and mostly helical elements on the convex side. 7 The ligand-binding domain forms a cupped-hand-like structure, with the palm of the hand representing the concave β-sheet surface of the LRR, the fingertips representing the N-terminal disulfide loop, and the opposable thumb representing the C-terminal disulfide loop 8 . The Cterminal disulfide loop, known as the β-switch, is the region crucial for the binding to the A1 domain of VWF 9 and it harbors five of the six GoF variants of GPIbα causing PT-VWD described so far: p.Trp246Leu (without signal peptide: p.Trp230Leu) 10 , p.Gly249Val (p.Gly233Val) 11 , p.Gly249Ser (p.Gly233Ser) 12 , p.Asp251Tyr (p.Asp235Tyr) 13 , p.Met255Val (p.Met239Val) 14 .…”

Section: Introductionmentioning

confidence: 99%

A p.Arg127Gln variant in GPIbα LRR5 allosterically enhances affinity for VWF: a novel form of platelet-type VWD

et al. 2022

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Gain-of-function (GoF) variants in GP1BA cause platelet-type von Willebrand disease (PT-VWD), a rare inherited autosomal dominant bleeding disorder characterized by enhanced platelet GPIbα-von Willebrand factor (VWF) interaction and thrombocytopenia. To date, only 6 variants causing PT-VWD have been described, 5 in the C-terminal disulfide loop of the VWF-binding domain of GPIbα and 1 in the macroglycopeptide. GoF GP1BA variants generate a high affinity conformation of the C-terminal disulfide loop with a consequent allosteric conformational change on another region of GPIbα, the leucine-rich-repeat (LRR) domain. We identified a novel GP1BA variant (p.Arg127Gln) affecting the LRR5 domain of GPIbα in a boy with easy bruising and laboratory test results suggestive of PT-VWD. We thus aimed to investigate the impact of the p.Arg127Gln variant on GPIbα affinity for VWF and on GPIbα structure. CHO cells expressing p.Arg127Gln GPIbα showed increased binding of VWF induced by ristocetin and enhanced tethering on immobilized VWF as compared with cells expressing wild-type (WT) GPIbα. Surface plasmon resonance confirmed that p.Arg127Gln enhances the binding affinity of GPIbα for VWF. Hydrogen-deuterium exchange mass spectrometryshowed that p.Arg127Gln of LRR, while having little effect on the dynamics of the LRR locally, enhances the conformational dynamics of the GPIbα C-terminal disulfide loop structure. Our data demonstrate for the first time that GoF variants outside the GPIbα C-terminal disulfide loop may be pathogenic and that aminoacidic changes in the LRR may cause allosterically conformational changes in the C-terminal disulfide loop of GPIbα inducing a conformation with high affinity for VWF.

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