HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Requirement of leucine-rich repeats of glycoprotein (GP) Iba for shear-dependent and static binding of von Willebrand factor to the platelet membrane GP Ib–IX-V complex

نویسندگان

  • Yang Shen
  • Gabriel M. Romo
  • Jing-fei Dong
  • Alicia Schade
  • Larry V. McIntire
  • Dermot Kenny
  • James C. Whisstock
  • Michael C. Berndt
  • José A. López
  • Robert K. Andrews
چکیده

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 Iba, which consist of an N-terminal flanking sequence (His-1– Ile-35), 7 leucine-rich repeats (Leu-36–Ala200), a C-terminal flank (Phe-201–Gly268), and a sulfated tyrosine sequence (Asp-269–Glu-282). We have used mammalian cell expression of canine–human chimeras of GP Iba, 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 Iba 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 Iba were identified as being critical for vWf adhesion to GP Ib–IX-V. (Blood. 2000;95:903910)

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Ristocetin-dependent, but not botrocetin-dependent, binding of von Willebrand factor to the platelet glycoprotein Ib-IX-V complex correlates with shear-dependent interactions

Under conditions of high shear stress, both hemostasis and thrombosis are initiated by the interaction of the platelet membrane glycoprotein (GP) Ib-IX-V complex with its adhesive ligand, von Willebrand factor (vWF), in the subendothelial matrix or plasma. This interaction involves the A1 domain of vWF and the N-terminal extracellular region of GP Iba (His-1-Glu-282), and it can also be induced...

متن کامل

Platelet glycoprotein Ib-IX as a regulator of systemic inflammation.

OBJECTIVE The platelet glycoprotein Ib-IX (GP Ib-IX) receptor is a well-characterized adhesion receptor supporting hemostasis and thrombosis via interactions with von Willebrand factor. We examine the GP Ib-IX/von Willebrand factor axis in murine polymicrobial sepsis, as modeled by cecal ligation and puncture (CLP). APPROACH AND RESULTS Genetic absence of the GP Ib-IX ligand, von Willebrand f...

متن کامل

HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Gain of von Willebrand factor–binding function by mutagenesis of a species-conserved residue within the leucine-rich repeat region of platelet glycoprotein Ib

Glycoprotein (GP) Ib , a member of the leucine-rich repeat (LRR) protein family, mediates platelet adhesion to immobilized von Willebrand factor (VWF). We investigated the role in VWF binding of charged residues in the LRR region of GP Ib that are conserved in human, canine, and murine proteins. Substitution of His86 with either Ala or Glu resulted in a gain of VWF-binding function as judged by...

متن کامل

HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The 1 helix– 13 strand spanning Leu214 to Val229 of platelet glycoprotein Ib facilitates the interaction with von Willebrand factor: evidence from characterization of the epitope of monoclonal antibody AP1

The glycoprotein Ib-IX-V (GP Ib-IX-V) complex mediates platelet binding to von Willebrand factor (VWF) through its largest polypeptide, GP Ib . Of the many GP Ib monoclonal antibodies described, AP1 is of particular interest because it blocks static VWF binding induced by 2 modulators, ristocetin and botrocetin, and platelet adhesion to VWF surfaces under flow. We mapped the AP1 binding site to...

متن کامل

HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Cytoskeletal regulation of the platelet glycoprotein Ib/V/IX–von Willebrand factor interaction

Shear-induced binding of von Willebrand factor (vWf) to the platelet glycoprotein (GP) Ib/V/IX complex plays a key role in initiating platelet adhesion and aggregation at sites of vascular injury. This study demonstrated that pretreating human platelets with inhibitors of actin polymerization, cytochalasin D or latrunculin B, dramatically enhances platelet aggregation induced by vWf. The effect...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره   شماره 

صفحات  -

تاریخ انتشار 2000