Crystal Structure of the Wild-type von Willebrand Factor A1-Glycoprotein Ibα Complex Reveals Conformation Differences with a Complex Bearing von Willebrand Disease Mutations

The adhesion of platelets to the subendothelium of blood vessels at sites of vascular injury under high shear conditions is mediated by a direct interaction between the platelet receptor glycoprotein Ibα (GpIbα) and the A1 domain of the von Willebrand factor (VWF). Here we report the 2.6-Å crystal structure of a complex comprised of the extracellular domain of GpIbα and the wild-type A1 domain of VWF. A direct comparison of this structure to a GpIbα-A1 complex containing “gain-of-function” mutations, A1-R543Q and GpIbα-M239V, reveals specific structural differences between these complexes at sites near the two GpIbα-A1 binding interfaces. At the smaller interface, differences in interaction show that the α1-β2 loop of A1 serves as a conformational switch, alternating between an open α1-β2 isomer that allows faster dissociation of GpIbα-A1, as observed in the wild-type complex, and an extended isomer that favors tight association as seen in the complex containing A1 with a type 2B von Willebrand Disease (VWD) mutation associated with spontaneous binding to GpIbα. At the larger interface, differences in interaction associated with the GpIbα-M239V platelet-type VWD mutation are minor and localized but feature discrete γ-turn conformers at the loop end of the β-hairpin structure. The β-hairpin, stabilized by a strong classic γ-turn as seen in the mutant complex, relates to the increased affinity of A1 binding, and the β-hairpin with a weak inverse γ-turn observed in the wild-type complex corresponds to the lower affinity state of GpIbα. These findings provide important details that add to our understanding of how both type 2B and platelet-type VWD mutations affect GpIbα-A1 binding affinity. The adhesion of platelets to the subendothelium of blood vessels at sites of vascular injury under high shear conditions is mediated by a direct interaction between the platelet receptor glycoprotein Ibα (GpIbα) and the A1 domain of the von Willebrand factor (VWF). Here we report the 2.6-Å crystal structure of a complex comprised of the extracellular domain of GpIbα and the wild-type A1 domain of VWF. A direct comparison of this structure to a GpIbα-A1 complex containing “gain-of-function” mutations, A1-R543Q and GpIbα-M239V, reveals specific structural differences between these complexes at sites near the two GpIbα-A1 binding interfaces. At the smaller interface, differences in interaction show that the α1-β2 loop of A1 serves as a conformational switch, alternating between an open α1-β2 isomer that allows faster dissociation of GpIbα-A1, as observed in the wild-type complex, and an extended isomer that favors tight association as seen in the complex containing A1 with a type 2B von Willebrand Disease (VWD) mutation associated with spontaneous binding to GpIbα. At the larger interface, differences in interaction associated with the GpIbα-M239V platelet-type VWD mutation are minor and localized but feature discrete γ-turn conformers at the loop end of the β-hairpin structure. The β-hairpin, stabilized by a strong classic γ-turn as seen in the mutant complex, relates to the increased affinity of A1 binding, and the β-hairpin with a weak inverse γ-turn observed in the wild-type complex corresponds to the lower affinity state of GpIbα. These findings provide important details that add to our understanding of how both type 2B and platelet-type VWD mutations affect GpIbα-A1 binding affinity. The adhesion of blood platelets to sites of vascular injury is mediated by von Willebrand factor (VWF), 1The abbreviations used are: VWF, von Willebrand factor; Gp, platelet glycoprotein receptor; VWD, von Willebrand disease.1The abbreviations used are: VWF, von Willebrand factor; Gp, platelet glycoprotein receptor; VWD, von Willebrand disease. a large multimeric plasma glycoprotein that binds to both exposed connective tissue and platelet surface receptors (1Sadler J.E. Annu. Rev. Biochem. 1998; 67: 395-424Crossref PubMed Scopus (1109) Google Scholar, 2Ruggeri Z.M. Curr. Opin. Hematol. 2003; 10: 142-149Crossref PubMed Scopus (106) Google Scholar). VWF is localized to the site of injury via attachment of its A3 domain to exposed collagen in the subendothelium (3Lankhof H. vanHoeij M. Shiphorst M.E. Bracke M. Wu Y.P. Ijsseldijk M.J. Vink T. deGroot P.G. Sixma J.J. Thromb. Haemostasis. 1996; 75: 950-958Crossref PubMed Scopus (130) Google Scholar). Subsequently, platelets are recruited through a direct interaction between the multimeric glycoprotein receptor complex GpIb-IX-V on the platelet surface, and the A1 domain of immobilized VWF (4Berndt M.C. Shen Y. Dopheide S.M. Gardiner E.E. Andrews R.K. Thromb. Haemostasis. 2001; 86: 178-188Crossref PubMed Scopus (238) Google Scholar). GpIb-IX-V is comprised of four transmembrane subunits, GpIbα, GpIbβ, GpIX, and GpV, and the binding site for A1 is localized to the extracellular domain of GpIbα (5Andrews R.K. Lopez J.A. Berndt M.C. Int. J. Biochem. Cell Biol. 1997; 29: 91-105Crossref PubMed Scopus (174) Google Scholar). There is no measurable binding of normal VWF to platelets in circulating blood, and the binding of VWF to GpIbα requires high shear conditions generated by rapidly flowing blood (6Savage B. Saldivar E. Ruggeri Z.M. Cell. 1996; 84: 289-297Abstract Full Text Full Text PDF PubMed Scopus (994) Google Scholar). At lower flow rates, platelet adhesion is independent of GpIbα and VWF and involves other adhesive interactions, including those between collagen and GpIa-IIa (integrin α2β1) (7Nieuwenhuis H.K. Akkerman J.W. Houdijk W.P. Sixma J.J. Nature. 1985; 318: 470-472Crossref PubMed Scopus (388) Google Scholar, 8Watson S.P. Gibbons J. Immunol. Today. 1998; 19: 260-264Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar) and those between fibrinogen and GpIIb-IIIa (integrin αIIbβ3) (6Savage B. Saldivar E. Ruggeri Z.M. Cell. 1996; 84: 289-297Abstract Full Text Full Text PDF PubMed Scopus (994) Google Scholar). In addition to its role in platelet adhesion, data from confocal videomicroscopic studies suggest that GpIbα-VWF association contributes to platelet aggregation and thrombus growth (9Savage B. Almus-Jacobs F. Ruggeri Z.M. Cell. 1998; 94: 657-666Abstract Full Text Full Text PDF PubMed Scopus (672) Google Scholar, 10Ruggeri Z.M. Dent J.A. Saldivar E. Blood. 1999; 94: 172-178Crossref PubMed Google Scholar). Von Willebrand disease (VWD) is the one of the most common congenital bleeding disorders with a prevalence of at least 100/million individuals (11Rodeghiero F. Castaman G. Dini E. Blood. 1987; 69: 454-459Crossref PubMed Google Scholar, 12Sadler J.E. Mannucci P.M. Berntorp E. Bochkov N. Boulyjenkov V. Ginsburg D. Meyer D. Peake I. Rodeghiero F. Srivastava A. Thromb. Haemostasis. 2000; 84: 160-174Crossref PubMed Scopus (442) Google Scholar). Type 2B VWD is caused by a qualitative abnormality of VWF in which normal sized multimers of VWF are secreted, and platelet-VWF interaction is augmented by increased affinity of VWF for GpIbα that does not require any mediating substance (13Ruggeri Z.M. Pareti F.I. Mannucci P.M. Ciavarella N. Zimmerman T.S. N. Engl. J. Med. 1980; 302: 1047-1051Crossref PubMed Scopus (267) Google Scholar, 14DeMarco L. Mazzucato M. DeRoia D. Casonato A. Fererici A.B. Girolami A. Ruggeri Z.M. J. Clin. Investig. 1990; 86: 785-792Crossref PubMed Scopus (33) Google Scholar). Paradoxically, this gain-of-function is associated with bleeding, perhaps because the largest multimers spontaneously associate with platelets, leaving the circulation deficient in large potent forms of VWF (13Ruggeri Z.M. Pareti F.I. Mannucci P.M. Ciavarella N. Zimmerman T.S. N. Engl. J. Med. 1980; 302: 1047-1051Crossref PubMed Scopus (267) Google Scholar, 15Ruggeri Z.M. Lombardi R. Gatti L. Bader R. Valsecchi C. Zimmerman T.S. Blood. 1982; 60: 1453-1456Crossref PubMed Google Scholar, 16DeMarco L. Girolami A. Zimmerman T.S. Ruggeri Z.M. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 7424-7428Crossref PubMed Scopus (96) Google Scholar). At least 14 distinct mutations are associated with type 2B VWD (1Sadler J.E. Annu. Rev. Biochem. 1998; 67: 395-424Crossref PubMed Scopus (1109) Google Scholar, 17Ginsberg D. Sadler J.E. Thromb. Haemostasis. 1993; 69: 177-184Crossref PubMed Scopus (193) Google Scholar, 18Budde U. Schneppenheim R. Rev. Clin. Exp. Hematol. 2001; 5: 335-368Crossref PubMed Scopus (54) Google Scholar), and most of these mutations cluster in a single disulfide loop of the VWF A1 domain between residues Cys509 and Cys695 (17Ginsberg D. Sadler J.E. Thromb. Haemostasis. 1993; 69: 177-184Crossref PubMed Scopus (193) Google Scholar, 19Fujimura Y. Titani K. Holland L.Z. Russell S.R. Roberts J.R. Elder J.H. Ruggeri Z.M. Zimmerman T.S. J. Biol. Chem. 1986; 261: 381-385Abstract Full Text PDF PubMed Google Scholar, 20Randi A.M. I. Mannucci P.M. Sadler J.E. J. Clin. Investig. PubMed Scopus Google Scholar, J.E. J. Biol. Chem. Full Text PDF PubMed Google Scholar). In a at VWF with type 2B mutations to platelets binding of wild-type VWF requires the of M. M. K. K. A. H. M. Y. K. Y. J. Clin. Investig. 1993; PubMed Scopus Google Scholar). studies M.C. Andrews R.K. PubMed Scopus Google Scholar, M. J. Biol. Chem. Full Text PDF PubMed Google Scholar, B. Meyer D. Blood. PubMed Google Scholar) show that this disulfide loop the binding sites for GpIbα, and VWD is associated with mutations in GpIbα that affinity for VWF in the of injury and shear including to Blood. 1993; PubMed Google Scholar, Thromb. Haemostasis. 1996; Scholar, T. M. T. H. M. K. H. Y. Blood. 1997; PubMed Google Scholar). with type 2B platelet-type VWD show including of high multimers of VWF in increased platelet bleeding and (13Ruggeri Z.M. Pareti F.I. Mannucci P.M. Ciavarella N. Zimmerman T.S. N. Engl. J. Med. 1980; 302: 1047-1051Crossref PubMed Scopus (267) Google Scholar, Thromb. Haemostasis. 1996; Scholar, Z.M. Zimmerman T.S. Blood. 1987; PubMed Google Scholar, Meyer D. R. G. J. N. Engl. J. Med. 1982; PubMed Scopus Google Scholar). binding studies G. A. J. Full Text Full Text PDF PubMed Scopus Google Scholar, G. A. Blood. 2003; PubMed Scopus Google Scholar) suggest that both disorders in GpIbα-VWF and of the VWF A1 domain the extracellular domain of GpIbα, and a complex comprised of gain-of-function of GpIbα and A1 J. M. R. R. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. J. J. Biol. Chem. Full Text Full Text PDF Scopus Google Scholar, S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). The of GpIbα of a domain of that is by a β-hairpin at the end and a disulfide loop and the at the end S. T. J. J. Biol. Chem. Full Text Full Text PDF Scopus Google Scholar, S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). and data two sites on the of GpIbα that with the β-hairpin and a loop at the end the which conformational binding of VWF S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar, T. Sadler J.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (130) Google Scholar, N. K. S. G. Lopez J.A. Berndt M.C. J. H. Blood. 2001; PubMed Scopus Google Scholar). on the structure and binding that type 2B VWD mutations the affinity of GpIbα-A1 interaction by the and of A1 that GpIbα binding S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). on the structure of A1 mutant that this mutation in the of A1 that in a affinity for GpIbα R. Ruggeri Z.M. Biol. 2000; PubMed Scopus Google Scholar). In binding studies of VWD that both type 2B and platelet-type VWD mutations platelet adhesion, in by the GpIbα-A1 dissociation G. A. J. Full Text Full Text PDF PubMed Scopus Google Scholar, G. A. Blood. 2003; PubMed Scopus Google Scholar). the structural for the of adhesion observed with VWD mutations and to specific associated with these mutations, we a complex comprised of the extracellular domain of GpIbα and the wild-type A1 domain of VWF and the structure at a 2.6-Å of this GpIbα-A1 structure with GpIbα, the A1 and the of the complex containing gain-of-function GpIbα-M239V and A1-R543Q reveals a conformational the of GpIbα and A1 that the binding of these The structural both mutations provide a for the observed binding in and residues of the GpIbα domain sites of and to the of via an and in The sites of are from the A1 binding from by GpIbα by of the with A. C. A. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). The GpIbα by on a and of and the used to the GpIbα structure. from the to the of GpIbα with two and the used for crystal The wild-type A1 domain from the VWF as in at the of in with at an of by the addition of and at at in The at at for The containing with and at at for The A1 domain to a at The a from to The and to to a of and the for at A1 to a The from the to a A1 a from to at The on a A1 a from to at A1 to by A complex containing GpIbα and A1 complex to by The of complexes of GpIbα and A1 by and to crystal and of a complex comprised of GpIbα and at in containing complex, of the GpIbα-A1 complex under conditions The the of with of a and to data to and in data the crystal at K. at the at the and 1997; Scopus Google Scholar) and D. PubMed Scopus Google Scholar). The structure with from at the sites by on the differences from a data The a E. G. 1997; PubMed Scopus Google Scholar). by as in D. PubMed Scopus Google for data and is the in for the of of is to but is for a of from the of of from is the in for the is to but is for a of from the in a with and an and data from to with J. M. T. D. 1998; PubMed Scopus Google Scholar). The which of GpIbα and of the VWF A1 domain as as a of and a of The is and are no of the of the generated M. J. Scopus Google Scholar) and The Scholar). of GpIbα-A1 and to GpIbα and crystal structure that the interaction between the wild-type A1 and GpIbα involves the binding as in the GpIbα-A1 complex comprised of mutant S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). seen in the mutant in the between GpIbα S. T. J. J. Biol. Chem. Full Text Full Text PDF Scopus Google Scholar, S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar) and GpIbα to A1 to the β-hairpin the and the studies Lopez J.A. PubMed Scopus (106) Google Scholar, M. Mazzucato M. L. J. Ruggeri Z.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Andrews R.K. Berndt M.C. 1996; PubMed Scopus Google Scholar) that the at the end of GpIbα is important for binding to VWF and an site of this is in the wild-type GpIbα-A1 as as in the mutant and that of this does not binding affinity to the A1 domain S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). The A1 domain to GpIbα for the conformational that is seen in and the end the end and the α1-β2 loop In our structure the disulfide that the A1 is but residues to and to are In the A1 structure an of residues at the end and at the end the site of GpIbα but the of these is not because of the of crystal residues these in the A1 J. M. R. R. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the and with is in our structure with in these and structural in the A1 in comparison of A1 and the mutant GpIbα-A1 complex S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). The of the α1-β2 loop in the complex containing wild-type A1 a which not in the mutant GpIbα-A1 complex, as in In wild-type the α1-β2 loop is by and is from GpIbα complex the α1-β2 loop of the A1 a that a with GpIbα and with receptor binding of and GpIbα-A1 GpIbα-A1 complex structure is in to that of the complex with a of a of a comparison of these reveals that with to the binding of these L. Mazzucato M. DeRoia D. Casonato A. Fererici A.B. Girolami A. Ruggeri Z.M. J. Clin. Investig. 1990; 86: 785-792Crossref PubMed Scopus (33) Google Scholar, G. A. Blood. 2003; PubMed Scopus Google Scholar, S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). in the α1-β2 of most differences between wild-type and mutant A1 are observed from the mutation These differences of the α1-β2 loop and residues that are in direct with GpIbα The single the of of structure in In both with at of these residues and in at the end of the associated with at the of its is to its in the mutant complex, the at the end of the a structural and the by to this the of which is for normal a on the of the A1 the of two direct with and a weak with from the of The of these and that not in the complex containing the The of residues and these between the and (integrin and the α1-β2 loop and to to and the α1-β2 The as a of the conformational on GpIbα binding, is and from GpIbα to a open a and the of the binding site The from the and the on the surface of the A1 domain and as the α1-β2 loop in and to important of the open In in the complex containing the the α1-β2 loop to the loop of A1 and GpIbα, a extended and the of the binding site a of this with the in mutant and the of the α1-β2 loop is in by the loop but not observed in our structure A and the of the as GpIbα binding, as wild-type A1 and its mutant including the α1-β2 and of this conformational the structural of the α1-β2 loop in the mutant complex In the of the α1-β2 loop in A1 J. M. R. R. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, R. Ruggeri Z.M. Biol. 2000; PubMed Scopus Google Scholar, K. 10: Full Text Full Text PDF PubMed Scopus Google Scholar) as the between open and extended seen in the wild-type and mutant a of the structural between A1 and residues at the end of GpIbα are from those in the mutant structure S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). in our structure the of from the loop to by GpIbα, that its is on the and direct with and In the mutant complex, is in direct with GpIbα-M239V, but its an extended and to residues of GpIbα, and in our structure on the surface of the α1-β2 with the of as and is from in the mutant complex the in the to a with S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). The structural role of the is to the extended of and to the gain-of-function with distinct for the open and extended of the α1-β2 as a at the of the A1 of A1-R543Q forms with and of in the wild-type complex these direct are as a of the and The of these residues from the site with the A1-R543Q mutant complex, a of two direct is observed on the wild-type complex The A1-R543Q mutation in an in the affinity of the A1 domain for GpIbα S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). other mutations associated with congenital VWD cluster in the α1-β2 including the of a at and at residues and (1Sadler J.E. Annu. Rev. Biochem. 1998; 67: 395-424Crossref PubMed Scopus (1109) Google Scholar, J.E. J. Biol. Chem. Full Text PDF PubMed Google Scholar). binding studies of the A1 domain in show that affinity is a of an in the GpIbα-A1 dissociation in A1 type 2B mutations and G. A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). with A1-R543Q a that interaction with GpIbα, wild-type A1 to in with the These structural differences from an conformational of the α1-β2 loop that an for this interaction the α1-β2 loop an important role in the binding affinity of by between an extended conformational isomer that a tight association under high as seen in the mutant complex, and an open isomer that faster dissociation of GpIbα-A1 under normal as observed in the wild-type in the mutant of A1 R. Ruggeri Z.M. Biol. 2000; PubMed Scopus Google Scholar). that the mutation GpIbα binding and the and of platelet adhesion in as a of the of the loop and of this loop by a The of this is not to with the GpIbα-A1 complex that in the wild-type complex the interaction is which is in the mutant complex S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). that the mutation is on the α1-β2 the of this mediated through of the α1-β2 loop to is seen in the A1-R543Q mutant The of type 2B mutations to A1 and the affinity associated with type 2B VWD to the that these mutations receptor binding by the of the which as of GpIbα binding J. M. R. R. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). role for the is with data that A1 this to GpIbα with affinity M. Dent J. R. J. Ruggeri Z.M. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar), as as with the of this in both wild-type and mutant S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). The of the A1 from the interaction site with of the α1-β2 as a of the conformational the for structural in this in the of but in GpIbα between the mutant receptor and receptors that the platelet-type VWD mutation are to two the which with A1 and the mutation and a the loop at a from the GpIbα-A1 interaction site The loop of GpIbα in the wild-type GpIbα-A1 complex a that that of GpIbα not S. T. J. J. Biol. Chem. Full Text Full Text PDF Scopus Google Scholar). this loop a in the mutant GpIbα-A1 complex S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar), and an of any of this is by observed crystal residues this loop in the mutant a comparison on the of structural near the mutation site in GpIbα and sites of as In the GpIbα-A1 complex the of GpIbα is to A1 to a between the two and S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). are observed between of GpIbα and of A1 in the wild-type structure and these are observed between the at the and in the mutant structure S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). the in which and are to the interface, the of is for with the In our the of is extended to a with and of A1 and with and of GpIbα not The of does not as as the and the observed are At the of the the in the of In in the mutant structure the of is the of the interface, in the wild-type structure is a in which the of the In the observed of the and a in the of the interface, in the of observed at this are in the two the because of the on the for the with the The structural in conformational at the end of the In both the two from the β-hairpin are by the of with one at the of the In the mutant the loop end of the β-hairpin a classic γ-turn by a strong between the of and the of These tight are to the end of to provide a in the J. Biol. 1993; PubMed Scopus Google Scholar, K. S. J. 2000; PubMed Google Scholar). In in our the β-hairpin loop an a γ-turn with interaction between the are as by C. PubMed Scopus Google Scholar), and at in these weak to as conformers that of E. R. K. R. J. Biol. PubMed Scopus Google Scholar, J. Biol. 1990; PubMed Scopus Google Scholar). differences in GpIbα-A1 interaction associated with the mutation are minor and localized and for the most that S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). conformational differences at the end of the β-hairpin are The mutation the affinity of A1 binding S. H. Sadler J.E. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) by the association with no in dissociation on the mutant complex structure that this mutation the of GpIbα-A1 association by the GpIbα for binding to A1 S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). In of this is observed that the gain-of-function mutant GpIbα-M239V a β-hairpin by a strong with the wild-type GpIbα that the β-hairpin structure but a weak these conformational differences an on binding affinity of GpIbα is to that the β-hairpin alternating between discrete conformational via γ-turn is an important structural factor in binding affinity of GpIbα. conformational for the affinity observed in GpIbα receptors with other platelet-type VWD mutations, as most of are the β-hairpin and Thromb. Haemostasis. 1996; Scholar, S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). GpIbα-A1 structure the of the GpIbα-VWF complex but an of a larger that of multimeric VWF, of the GpIb-IX-V receptor complex, and studies show that GpIbα a lower affinity for multimeric VWF for the A1 domain which that in VWF an role in binding S. Shiphorst M.E. P.G. Sixma J.J. PubMed Scopus Google Scholar). studies T. Sadler J.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (130) Google Scholar, M. Dent J. R. J. Ruggeri Z.M. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar, M. H. Ruggeri Z.M. J. Biol. Chem. Full Text PDF PubMed Google Scholar, S. Ruggeri Z.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) that the of the A1 a on binding affinity and that to from to and from to the and of the A1 in our to VWF binding to H. Y. M. A. Ruggeri Z.M. Zimmerman T.S. J. Biol. Chem. Full Text PDF PubMed Google Scholar). an immobilized A1 that and with platelets in a to multimeric VWF, in this a interaction with GpIbα S. Ruggeri Z.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In a A1 does not to platelets at high shear rates, binding to GpIbα is observed under shear S. Ruggeri Z.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). a of VWF that the domain is to VWF binding to GpIbα but does not platelets R.K. J.J. Berndt M.C. PubMed Scopus Google Scholar), which is with the of a interaction site between GpIbα and VWF for the domain of GpIbα in the of the A1 binding as studies Lopez J.A. Thromb. Haemostasis. PubMed Scopus Google Scholar) that platelets a mutant GpIbα receptor residues to the are to to immobilized VWF under are of both GpIbα and VWF not in our structure that are for binding and and the wild-type structure the mutant structure the of binding that between these is that an multimeric GpIbα-VWF to the complexes R. Roberts J.R. J. Ruggeri Z.M. 2003; PubMed Scopus (166) Google Scholar, J.J. R. J. L. 2003; PubMed Scopus Google Scholar), as platelets to VWF and with other platelet adhesion and the of the GpIbα-VWF complex, the wild-type in comparison with the mutant reveals details of specific important that as a of both type 2B and platelet-type VWD These are to provide a the of GpIbα-A1 binding affinity. differences in both the α1-β2 loop of A1 and the γ-turn of GpIbα how the binding affinity of the GpIbα-A1 interaction by through at the binding an for VWF binding to platelets in for growth of for and at for with data

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.