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Mapping of the ligand-binding site on the b ' domain of human PDI: interaction with peptide ligands and the x-linker region
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Byrne, Lee J., Sidhu, Ateesh, Wallis, A. Katrine, Ruddock, Lloyd W., Freedman, R. B., Howard, Mark J. and Williamson, Richard A. (2009) Mapping of the ligand-binding site on the b ' domain of human PDI: interaction with peptide ligands and the x-linker region. Biochemical Journal, Vol.423 (No.2). pp. 209-217. doi:10.1042/BJ20090565 ISSN 0264-6021.
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Official URL: http://dx.doi.org/10.1042/BJ20090565
Abstract
PDI (protein disulfide-isomerase) catalyses the formation of native disulfide bonds of secretory proteins in the endoplasmic reticulum. PDI consists of four thioredoxin-like domains, of which two contain redox-active catalytic sites (a and a'), and two do not (b and b'). The b' domain is primarily responsible for substrate binding, although the nature and specificity of the substrate-binding site is still poorly understood. In the present study, we show that the W domain of human PDI is in conformational exchange, but that its structure is stabilized by the addition of peptide ligands or by binding the x-linker region. The location of the ligand-binding site in b' was mapped by NMR chemical shift perturbation and found to consist primarily of residues from the core beta-sheet and alpha-helices 1 and 3. This site is where the x-linker region binds in the X-ray structure of b'x and we show that peptide ligands can compete with x binding at this site. The finding that x binds in the principal ligand-binding site of W further supports the hypothesis that x functions to gate access to this site and so modulates PDI activity.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | Q Science > QD Chemistry | ||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) > Biological Sciences ( -2010) | ||||
| Journal or Publication Title: | Biochemical Journal | ||||
| Publisher: | Portland Press | ||||
| ISSN: | 0264-6021 | ||||
| Official Date: | 15 October 2009 | ||||
| Dates: |
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| Volume: | Vol.423 | ||||
| Number: | No.2 | ||||
| Number of Pages: | 9 | ||||
| Page Range: | pp. 209-217 | ||||
| DOI: | 10.1042/BJ20090565 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC) | ||||
| Grant number: | BB/D018072 (BBSRC) |
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