title: Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases.
abstract: Mutations in the ultralong vascular protein von Willebrand factor (VWF) cause the common human bleeding disorder, von Willebrand disease (VWD). The A1 domain in VWF binds to glycoprotein Ibα (GPIbα) on platelets, in a reaction triggered, in part, by alterations in flow during bleeding. Gain-of-function mutations in A1 and GPIbα in VWD suggest conformational regulation. We report that force application switches A1 and/or GPIbα to a second state with faster on-rate, providing a mechanism for activating VWF binding to platelets. Switching occurs near 10 pN, a force that also induces a state of the receptor-ligand complex with slower off-rate. Force greatly increases the effects of VWD mutations, explaining pathophysiology. Conversion of single molecule kon (s(-1)) to bulk phase kon (s(-1)M(-1)) and the kon and koff values extrapolated to zero force for the low-force pathways show remarkably good agreement with bulk-phase measurements.
authors: Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
authors: Jongseong
authors: J
authors: Kim
authors: Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
authors: Nathan E
authors: NE
authors: Hudson
authors: Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 Timothy.Springer@childrens.harvard.edu.
authors: Timothy A
authors: TA
authors: Springer
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000378:metabolism; D006801:Humans; D057446:Hydrodynamics; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013314:Stress, Mechanical; D013997:Time Factors; D014842:von Willebrand Diseases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D014841:von Willebrand Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor