The disulfide bond Cys2724-Cys2774 in the C-terminal cystine knot domain of von Willebrand factor is critical for its dimerization and secretion

Abstract Background Type 3 von Willebrand disease (VWD) exhibits severe hemorrhagic tendency with complicated pathogenesis. The C-terminal cystine knot (CTCK) domain plays an important role in the dimerization and secretion of von Willebrand factor (VWF). The CTCK domain has four intrachain disulfid...

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Autores principales:	Yuxin Zhang, Fengwu Chen, Aizhen Yang, Xiaoying Wang, Yue Han, Depei Wu, Yi Wu, Jingyu Zhang
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	von Willebrand factor (VWF) von Willebrand disease (VWD) cystine knot domain multimerization disulfide bond Diseases of the blood and blood-forming organs RC633-647.5
Acceso en línea:	https://doaj.org/article/c84d61ee1817497bac5ef6a4fe74e544
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spelling	oai:doaj.org-article:c84d61ee1817497bac5ef6a4fe74e5442021-11-28T12:25:33ZThe disulfide bond Cys2724-Cys2774 in the C-terminal cystine knot domain of von Willebrand factor is critical for its dimerization and secretion10.1186/s12959-021-00348-w1477-9560https://doaj.org/article/c84d61ee1817497bac5ef6a4fe74e5442021-11-01T00:00:00Zhttps://doi.org/10.1186/s12959-021-00348-whttps://doaj.org/toc/1477-9560Abstract Background Type 3 von Willebrand disease (VWD) exhibits severe hemorrhagic tendency with complicated pathogenesis. The C-terminal cystine knot (CTCK) domain plays an important role in the dimerization and secretion of von Willebrand factor (VWF). The CTCK domain has four intrachain disulfide bonds including Cys2724-Cys2774, Cys2739-Cys2788, Cys2750-Cys2804 and Cys2754-Cys2806, and the single cysteine mutation in Cys2739-Cys2788, Cys2750-Cys2804 and Cys2754-Cys2806 result in type 3 VWD, demonstrating the crucial role of these three disulfide bonds in VWF biosynthesis, however, the role of the remaining disulfide bond Cys2724-Cys2774 remains unclear. Method and results In this study, by the next-generation sequencing we found a missense mutation a c.8171G>A (C2724Y) in the CTCK domain of VWF allele in a patient family with type 3 VWD. In vitro, VWF C2724Y protein was expressed normally in HEK-293T cells but did not form a dimer or secrete into cell culture medium, suggesting that C2724 is critical for the VWF dimerization, and thus for VWF multimerization and secretion. Conclusions Our findings provide the first genetic evidence for the important role of Cys2724-Cys2774 in VWF biosynthesis and secretion. Therefore, all of the four intrachain disulfide bonds in CTCK monomer contribute to VWF dimerization and secretion.Yuxin ZhangFengwu ChenAizhen YangXiaoying WangYue HanDepei WuYi WuJingyu ZhangBMCarticlevon Willebrand factor (VWF)von Willebrand disease (VWD)cystine knot domainmultimerizationdisulfide bondDiseases of the blood and blood-forming organsRC633-647.5ENThrombosis Journal, Vol 19, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	von Willebrand factor (VWF) von Willebrand disease (VWD) cystine knot domain multimerization disulfide bond Diseases of the blood and blood-forming organs RC633-647.5
spellingShingle	von Willebrand factor (VWF) von Willebrand disease (VWD) cystine knot domain multimerization disulfide bond Diseases of the blood and blood-forming organs RC633-647.5 Yuxin Zhang Fengwu Chen Aizhen Yang Xiaoying Wang Yue Han Depei Wu Yi Wu Jingyu Zhang The disulfide bond Cys2724-Cys2774 in the C-terminal cystine knot domain of von Willebrand factor is critical for its dimerization and secretion
description	Abstract Background Type 3 von Willebrand disease (VWD) exhibits severe hemorrhagic tendency with complicated pathogenesis. The C-terminal cystine knot (CTCK) domain plays an important role in the dimerization and secretion of von Willebrand factor (VWF). The CTCK domain has four intrachain disulfide bonds including Cys2724-Cys2774, Cys2739-Cys2788, Cys2750-Cys2804 and Cys2754-Cys2806, and the single cysteine mutation in Cys2739-Cys2788, Cys2750-Cys2804 and Cys2754-Cys2806 result in type 3 VWD, demonstrating the crucial role of these three disulfide bonds in VWF biosynthesis, however, the role of the remaining disulfide bond Cys2724-Cys2774 remains unclear. Method and results In this study, by the next-generation sequencing we found a missense mutation a c.8171G>A (C2724Y) in the CTCK domain of VWF allele in a patient family with type 3 VWD. In vitro, VWF C2724Y protein was expressed normally in HEK-293T cells but did not form a dimer or secrete into cell culture medium, suggesting that C2724 is critical for the VWF dimerization, and thus for VWF multimerization and secretion. Conclusions Our findings provide the first genetic evidence for the important role of Cys2724-Cys2774 in VWF biosynthesis and secretion. Therefore, all of the four intrachain disulfide bonds in CTCK monomer contribute to VWF dimerization and secretion.
format	article
author	Yuxin Zhang Fengwu Chen Aizhen Yang Xiaoying Wang Yue Han Depei Wu Yi Wu Jingyu Zhang
author_facet	Yuxin Zhang Fengwu Chen Aizhen Yang Xiaoying Wang Yue Han Depei Wu Yi Wu Jingyu Zhang
author_sort	Yuxin Zhang
title	The disulfide bond Cys2724-Cys2774 in the C-terminal cystine knot domain of von Willebrand factor is critical for its dimerization and secretion
title_short	The disulfide bond Cys2724-Cys2774 in the C-terminal cystine knot domain of von Willebrand factor is critical for its dimerization and secretion
title_full	The disulfide bond Cys2724-Cys2774 in the C-terminal cystine knot domain of von Willebrand factor is critical for its dimerization and secretion
title_fullStr	The disulfide bond Cys2724-Cys2774 in the C-terminal cystine knot domain of von Willebrand factor is critical for its dimerization and secretion
title_full_unstemmed	The disulfide bond Cys2724-Cys2774 in the C-terminal cystine knot domain of von Willebrand factor is critical for its dimerization and secretion
title_sort	disulfide bond cys2724-cys2774 in the c-terminal cystine knot domain of von willebrand factor is critical for its dimerization and secretion
publisher	BMC
publishDate	2021
url	https://doaj.org/article/c84d61ee1817497bac5ef6a4fe74e544
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The disulfide bond Cys2724-Cys2774 in the C-terminal cystine knot domain of von Willebrand factor is critical for its dimerization and secretion

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