Evidence for the Misfolding of the A1 Domain within Multimeric von Willebrand Factor in Type 2 von Willebrand Disease.
Amino Acid Substitution
Blood Platelets
/ chemistry
Gene Expression Regulation
/ genetics
HEK293 Cells
Humans
Loss of Function Mutation
/ genetics
Mass Spectrometry
Protein Domains
/ genetics
Protein Folding
Protein Multimerization
/ genetics
Protein Structure, Secondary
/ genetics
Proteostasis Deficiencies
/ blood
von Willebrand Disease, Type 2
/ blood
von Willebrand Factor
/ chemistry
Hydrogen-deuterium exchange mass spectrometry
Limited proteolysis
Local disorder
Protein misfolding
von Willebrand factor
Journal
Journal of molecular biology
ISSN: 1089-8638
Titre abrégé: J Mol Biol
Pays: Netherlands
ID NLM: 2985088R
Informations de publication
Date de publication:
17 01 2020
17 01 2020
Historique:
received:
15
07
2019
revised:
13
09
2019
accepted:
24
09
2019
pubmed:
20
10
2019
medline:
1
7
2020
entrez:
20
10
2019
Statut:
ppublish
Résumé
Von Willebrand factor (VWF), an exceptionally large multimeric plasma glycoprotein, functions to initiate coagulation by agglutinating platelets in the blood stream to sites of vascular injury. This primary hemostatic function is perturbed in type 2 dysfunctional subtypes of von Willebrand disease (VWD) by mutations that alter the structure and function of the platelet GPIbα adhesive VWF A1 domains. The resulting amino acid substitutions cause local disorder and misfold the native structure of the isolated platelet GPIbα-adhesive A1 domain of VWF in both gain-of-function (type 2B) and loss-of-function (type 2M) phenotypes. These structural effects have not been explicitly observed in A1 domains of VWF multimers native to blood plasma. New mass spectrometry strategies are applied to resolve the structural effects of 2B and 2M mutations in VWF to verify the presence of A1 domain structural disorder in multimeric VWF harboring type 2 VWD mutations. Limited trypsinolysis mass spectrometry (LTMS) and hydrogen-deuterium exchange mass spectrometry (HXMS) are applied to wild-type and VWD variants of the single A1, A2, and A3 domains, an A1A2A3 tridomain fragment of VWF, plasmin-cleaved dimers of VWF, multimeric recombinant VWF, and normal VWF plasma concentrates. Comparatively, these methods show that mutations known to misfold the isolated A1 domain increase the rate of trypsinolysis and the extent of hydrogen-deuterium exchange in local secondary structures of A1 within multimeric VWF. VWD mutation effects are localized to the A1 domain without appreciably affecting the structure and dynamics of other VWF domains. The intrinsic dynamics of A1 observed in recombinant fragments of VWF are conserved in plasma-derived VWF. These studies reveal that structural disorder does occur in VWD variants of the A1 domain within multimeric VWF and provides strong support for VWF misfolding as a result of some, but not all, type 2 VWD variants.
Identifiants
pubmed: 31628947
pii: S0022-2836(19)30577-7
doi: 10.1016/j.jmb.2019.09.022
pmc: PMC7028320
mid: NIHMS1544415
pii:
doi:
Substances chimiques
von Willebrand Factor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
305-323Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL109109
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL146508
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000135
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
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