title: Identification of a juxtamembrane mechanosensitive domain in the platelet mechanosensor glycoprotein Ib-IX complex.
abstract: How glycoprotein (GP)Ib-IX complex on the platelet surface senses the blood flow through its binding to the plasma protein von Willebrand factor (VWF) and transmits a signal into the platelet remains unclear. Here we show that optical tweezer-controlled pulling of the A1 domain of VWF (VWF-A1) on GPIb-IX captured by its cytoplasmic domain induced unfolding of a hitherto unidentified structural domain before the dissociation of VWF-A1 from GPIb-IX. Additional studies using recombinant proteins and mutant complexes confirmed its existence in GPIb-IX and enabled localization of this quasi-stable mechanosensitive domain of ∼60 residues between the macroglycopeptide region and the transmembrane helix of the GPIbα subunit. These results suggest that VWF-mediated pulling under fluid shear induces unfolding of the mechanosensitive domain in GPIb-IX, which may possibly contribute to platelet mechanosensing and/or shear resistance of VWF-platelet interaction. The identification of the mechanosensitive domain in GPIb-IX has significant implications for the pathogenesis and treatment of related blood diseases.
authors.affiliation: Department of Mechanical Engineering and Mechanics, Bioengineering Program, Lehigh University, Bethlehem, PA;
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA;
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
authors.affiliation: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA;
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Mechanical Engineering and Mechanics, Bioengineering Program, Lehigh University, Bethlehem, PA;
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX; and.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yang
authors.affiliation: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA;
authors.forename: Xin
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Mechanical Engineering and Mechanics, Bioengineering Program, Lehigh University, Bethlehem, PA;
authors.forename: Yizhen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Puget Sound Blood Center, Seattle, WA.
authors.forename: John D
authors.initials: JD
authors.lastname: Kulman
authors.affiliation: Department of Mechanical Engineering and Mechanics, Bioengineering Program, Lehigh University, Bethlehem, PA;
authors.forename: X Frank
authors.initials: XF
authors.lastname: Zhang
authors.affiliation: Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA;
authors.forename: Renhao
authors.initials: R
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001792:Blood Platelets / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002942:Circular Dichroism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010973:Platelet Adhesiveness; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical; D014841:von Willebrand Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D019038:Platelet Glycoprotein GPIb-IX Complex; D011994:Recombinant Proteins; D014841:von Willebrand Factor