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Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping

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Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping. / Tischer, Alexander; Machha, Venkata R; Frontroth, Juan P; Brehm, Maria A; Obser, Tobias; Schneppenheim, Reinhard; Mayne, Leland; Walter Englander, S; Auton, Matthew.

in: J MOL BIOL, Jahrgang 429, Nr. 14, 07.07.2017, S. 2161-2177.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Tischer, A, Machha, VR, Frontroth, JP, Brehm, MA, Obser, T, Schneppenheim, R, Mayne, L, Walter Englander, S & Auton, M 2017, 'Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping', J MOL BIOL, Jg. 429, Nr. 14, S. 2161-2177. https://doi.org/10.1016/j.jmb.2017.05.013

APA

Tischer, A., Machha, V. R., Frontroth, J. P., Brehm, M. A., Obser, T., Schneppenheim, R., Mayne, L., Walter Englander, S., & Auton, M. (2017). Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping. J MOL BIOL, 429(14), 2161-2177. https://doi.org/10.1016/j.jmb.2017.05.013

Vancouver

Tischer A, Machha VR, Frontroth JP, Brehm MA, Obser T, Schneppenheim R et al. Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping. J MOL BIOL. 2017 Jul 7;429(14):2161-2177. https://doi.org/10.1016/j.jmb.2017.05.013

Bibtex

@article{9cbbe7a981354ad38a68d28e244afd48,
title = "Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping",
abstract = "Mutation of the cysteines forming the disulfide loop of the platelet GPIbα adhesive A1 domain of von Willebrand factor (VWF) causes quantitative VWF deficiencies in the blood and von Willebrand disease. We report two cases of transient severe thrombocytopenia induced by DDAVP treatment. Cys1272Trp and Cys1458Tyr mutations identified by genetic sequencing implicate an abnormal gain-of-function phenotype, evidenced by thrombocytopenia, which quickly relapses back to normal platelet counts and deficient plasma VWF. Using surface plasmon resonance, analytical rheology, and hydrogen-deuterium exchange mass spectrometry (HXMS), we decipher mechanisms of A1-GPIbα-mediated platelet adhesion and resolve dynamic secondary structure elements that regulate the binding pathway. Constrained by the disulfide, conformational selection between weak and tight binding states of A1 takes precedence and drives normal platelet adhesion to VWF. Less restrained through mutation, loss of the disulfide preferentially diverts binding through an induced-fit disease pathway enabling high-affinity GPIbα binding and firm platelet adhesion to a partially disordered A1 domain. HXMS reveals a dynamic asymmetry of flexible and ordered regions common to both variants, indicating that the partially disordered A1 lacking the disulfide retains native-like structural dynamics. Both binding mechanisms share common structural and thermodynamic properties, but the enhanced local disorder in the disease state perpetuates high-affinity platelet agglutination, characteristic of type 2B VWD, upon DDAVP-stimulated secretion of VWF leading to transient thrombocytopenia and a subsequent deficiency of plasma VWF, characteristic of type 2A VWD.",
keywords = "Amino Acid Substitution, Child, Cysteine, Deamino Arginine Vasopressin, Disulfides, Female, Humans, Mass Spectrometry, Mutant Proteins, Mutation, Missense, Platelet Aggregation, Platelet Glycoprotein GPIb-IX Complex, Plethysmography, Impedance, Surface Plasmon Resonance, Thrombocytopenia, von Willebrand Factor, Case Reports, Journal Article",
author = "Alexander Tischer and Machha, {Venkata R} and Frontroth, {Juan P} and Brehm, {Maria A} and Tobias Obser and Reinhard Schneppenheim and Leland Mayne and {Walter Englander}, S and Matthew Auton",
note = "Copyright {\textcopyright} 2017 Elsevier Ltd. All rights reserved.",
year = "2017",
month = jul,
day = "7",
doi = "10.1016/j.jmb.2017.05.013",
language = "English",
volume = "429",
pages = "2161--2177",
journal = "J MOL BIOL",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "14",

}

RIS

TY - JOUR

T1 - Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping

AU - Tischer, Alexander

AU - Machha, Venkata R

AU - Frontroth, Juan P

AU - Brehm, Maria A

AU - Obser, Tobias

AU - Schneppenheim, Reinhard

AU - Mayne, Leland

AU - Walter Englander, S

AU - Auton, Matthew

N1 - Copyright © 2017 Elsevier Ltd. All rights reserved.

PY - 2017/7/7

Y1 - 2017/7/7

N2 - Mutation of the cysteines forming the disulfide loop of the platelet GPIbα adhesive A1 domain of von Willebrand factor (VWF) causes quantitative VWF deficiencies in the blood and von Willebrand disease. We report two cases of transient severe thrombocytopenia induced by DDAVP treatment. Cys1272Trp and Cys1458Tyr mutations identified by genetic sequencing implicate an abnormal gain-of-function phenotype, evidenced by thrombocytopenia, which quickly relapses back to normal platelet counts and deficient plasma VWF. Using surface plasmon resonance, analytical rheology, and hydrogen-deuterium exchange mass spectrometry (HXMS), we decipher mechanisms of A1-GPIbα-mediated platelet adhesion and resolve dynamic secondary structure elements that regulate the binding pathway. Constrained by the disulfide, conformational selection between weak and tight binding states of A1 takes precedence and drives normal platelet adhesion to VWF. Less restrained through mutation, loss of the disulfide preferentially diverts binding through an induced-fit disease pathway enabling high-affinity GPIbα binding and firm platelet adhesion to a partially disordered A1 domain. HXMS reveals a dynamic asymmetry of flexible and ordered regions common to both variants, indicating that the partially disordered A1 lacking the disulfide retains native-like structural dynamics. Both binding mechanisms share common structural and thermodynamic properties, but the enhanced local disorder in the disease state perpetuates high-affinity platelet agglutination, characteristic of type 2B VWD, upon DDAVP-stimulated secretion of VWF leading to transient thrombocytopenia and a subsequent deficiency of plasma VWF, characteristic of type 2A VWD.

AB - Mutation of the cysteines forming the disulfide loop of the platelet GPIbα adhesive A1 domain of von Willebrand factor (VWF) causes quantitative VWF deficiencies in the blood and von Willebrand disease. We report two cases of transient severe thrombocytopenia induced by DDAVP treatment. Cys1272Trp and Cys1458Tyr mutations identified by genetic sequencing implicate an abnormal gain-of-function phenotype, evidenced by thrombocytopenia, which quickly relapses back to normal platelet counts and deficient plasma VWF. Using surface plasmon resonance, analytical rheology, and hydrogen-deuterium exchange mass spectrometry (HXMS), we decipher mechanisms of A1-GPIbα-mediated platelet adhesion and resolve dynamic secondary structure elements that regulate the binding pathway. Constrained by the disulfide, conformational selection between weak and tight binding states of A1 takes precedence and drives normal platelet adhesion to VWF. Less restrained through mutation, loss of the disulfide preferentially diverts binding through an induced-fit disease pathway enabling high-affinity GPIbα binding and firm platelet adhesion to a partially disordered A1 domain. HXMS reveals a dynamic asymmetry of flexible and ordered regions common to both variants, indicating that the partially disordered A1 lacking the disulfide retains native-like structural dynamics. Both binding mechanisms share common structural and thermodynamic properties, but the enhanced local disorder in the disease state perpetuates high-affinity platelet agglutination, characteristic of type 2B VWD, upon DDAVP-stimulated secretion of VWF leading to transient thrombocytopenia and a subsequent deficiency of plasma VWF, characteristic of type 2A VWD.

KW - Amino Acid Substitution

KW - Child

KW - Cysteine

KW - Deamino Arginine Vasopressin

KW - Disulfides

KW - Female

KW - Humans

KW - Mass Spectrometry

KW - Mutant Proteins

KW - Mutation, Missense

KW - Platelet Aggregation

KW - Platelet Glycoprotein GPIb-IX Complex

KW - Plethysmography, Impedance

KW - Surface Plasmon Resonance

KW - Thrombocytopenia

KW - von Willebrand Factor

KW - Case Reports

KW - Journal Article

U2 - 10.1016/j.jmb.2017.05.013

DO - 10.1016/j.jmb.2017.05.013

M3 - SCORING: Journal article

C2 - 28533135

VL - 429

SP - 2161

EP - 2177

JO - J MOL BIOL

JF - J MOL BIOL

SN - 0022-2836

IS - 14

ER -