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Plasticity of human protein disulfide isomerase : evidence for mobility around the x-linker region and its functional significance

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Wang, Chao, Chen, Sihong, Wang, Xi, Wang, Lei, Wallis, A. Katrine, Freedman, R. B. and Wang, Chih-chen. (2010) Plasticity of human protein disulfide isomerase : evidence for mobility around the x-linker region and its functional significance. Journal of Biological Chemistry, Vol.285 (No.35). pp. 26788-26797. ISSN 0021-9258

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Official URL: http://dx.doi.org/10.1074/jbc.M110.107839

Abstract

Protein disulfide isomerase (PDI), which consists of multiple domains arranged as abb'xa'c, is a key enzyme responsible for oxidative folding in the endoplasmic reticulum. In this work we focus on the conformational plasticity of this enzyme. Proteolysis of native human PDI (hPDI) by several proteases consistently targets sites in the C-terminal half of the molecule (x-linker and a' domain) leaving large fragments in which the N terminus is intact. Fluorescence studies on the W111F/W390F mutant of full-length PDI show that its fluorescence is dominated by Trp-347 in the x-linker which acts as an intrinsic reporter and indicates that this linker can move between "capped" and "uncapped" conformations in which it either occupies or exposes the major ligand binding site on the b' domain of hPDI. Studies with a range of constructs and mutants using intrinsic fluorescence, collision quenching, and extrinsic probe fluorescence (1-anilino-8-naphthalene sulfonate) show that the presence of the a' domain in full-length hPDI moderates the ability of the x-linker to generate the capped conformation (compared with shorter fragments) but does not abolish it. Hence, unlike yeast PDI, the major conformational plasticity of full-length hPDI concerns the mobility of the a' domain "arm" relative to the bb' "trunk" mediated by the x-linker. The chaperone and enzymatic activities of these constructs and mutants are consistent with the interpretation that the reversible interaction of the x-linker with the ligand binding site mediates access of protein substrates to this site.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology
Divisions:	Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010)
Library of Congress Subject Headings (LCSH):	Protein disulfide isomerase, Adaptation (Physiology)
Journal or Publication Title:	Journal of Biological Chemistry
Publisher:	American Society of Biochemistry and Molecular Biology Inc.
ISSN:	0021-9258
Date:	27 August 2010
Volume:	Vol.285
Number:	No.35
Number of Pages:	10
Page Range:	pp. 26788-26797
Identification Number:	10.1074/jbc.M110.107839
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), China. Guo jia ke xue ji shu bu [Ministry of Science and Technology], Zhongguo ke xue yuan [Chinese Academy of Sciences] (CAS), Wellcome Trust (London, England)
Grant number:	2006CB806508 (MST), 2006CB910903 (MST), KSCX2-YW-R-119 (CAS), KSCX2-YW-R-256 (CAS), BB/D017807 (BBSRC), CPA1339 (BBSRC)
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URI:	http://wrap.warwick.ac.uk/id/eprint/5302