Requirement of leucine-rich repeats of glycoprotein (GP) Ibα for shear-dependent and static binding of von Willebrand factor to the platelet membrane GP Ib–IX-V complex

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Abstract
The platelet glycoprotein (GP) Ib–IX-V complex mediates adhesion to von Willebrand factor (vWf) in (patho)physiologic thrombus formation. The vWf-binding site on GP Ib–IX-V is within the N-terminal 282 residues of GP Ib, which consist of an N-terminal flanking sequence (His-1–Ile-35), 7 leucine-rich repeats (Leu-36–Ala-200), a C-terminal flank (Phe-201–Gly-268), and a sulfated tyrosine sequence (Asp-269–Glu-282). We have used mammalian cell expression of canine–human chimeras of GP Ib, corresponding to precise structural boundaries, to demonstrate the first specific requirement for individual leucine-rich repeats for binding of vWf either induced by a modulator, ristocetin, or under hydrodynamic flow. Implicit in this approach was that the GP Ib chimeras retained a functional conformation, a supposition confirmed by analyzing restoration of function to reversed human–canine chimeras and demonstrating that all chimeras bound vWf activated by botrocetin, a modulator that is indiscriminate between species. Leucine-rich repeats 2, 3, and 4 of GP Ib were identified as being critical for vWf adhesion to GP Ib–IX-V.

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