N-linked glycan stabilization of the VWF A2 domain.

Blood
Christopher J Lynch, David A Lane

Abstract

Shear forces in the blood trigger a conformational transition in the von Willebrand factor (VWF) A2 domain, from its native folded to an unfolded state, in which the cryptic scissile bond (Y1605-M1606) is exposed and can then be proteolysed by ADAMTS13. The conformational transition depends upon a Ca(2+)binding site and a vicinal cysteine disulfide bond. Glycosylation at N1574 has previously been suggested to modulate VWF A2 domain interaction with ADAMTS13 through steric hindrance by the bulky carbohydrate structure. We investigated how the N-linked glycans of the VWF A2 domain affect thermostability and regulate both the exposure of the ADAMTS13 binding sites and the scissile bond. We show by differential scanning fluorimetry that the N-linked glycans thermodynamically stabilize the VWF A2 domain. The essential component of the glycan structure is the first sugar residue (GlcNAc) at the N1574 attachment site. From its crystal structures, N1574-GlcNAc is predicted to form stabilizing intradomain interactions with Y1544 and nearby residues. Substitution of the surface-exposed Y1544 to aspartic acid is able to stabilize the domain in the absence of glycosylation and protect against ADAMTS13 proteolysis in both the VWF A2 domain ...Continue Reading

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Citations

Jul 12, 2017·Journal of Proteome Research·Ebtesam A GashashPeng George Wang
Jul 28, 2018·Journal of Thrombosis and Haemostasis : JTH·W DengR Li
Mar 11, 2017·Arteriosclerosis, Thrombosis, and Vascular Biology·Teresa M BrophyJames S O'Donnell
Feb 15, 2019·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Henry P IgidDonald P Quick
Sep 4, 2019·Journal of Thrombosis and Haemostasis : JTH·Alexander TischerMatthew Auton
Mar 7, 2018·Science Advances·Diego ButeraPhilip J Hogg
Nov 7, 2017·Journal of Thrombosis and Haemostasis : JTH·K South, D A Lane
Oct 3, 2019·The Journal of Chemical Physics·Chuqiao DongEdmund B Webb
Sep 17, 2021·Journal of Thrombosis and Haemostasis : JTH·Kayleigh M VoosRenhao Li

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