Peptide binding induces large scale changes in inter-domain mobility in human Pin1
- Pin1 is a peptidyl-prolyl cis/trans isomerase (PPIase) essential for cell cycle regulation. Pin1-catalyzed peptidyl-prolyl isomerization provides a key conformational switch to activate phosphorylation sites with the common phospho-Ser/Thr-Pro sequence motif. This motif is ubiquitously exploited in cellular response to a variety of signals. Pin1 is able to bind phospho-Ser/Thr-Pro-containing sequences at two different sites that compete for the same substrate. One binding site is located within the N-terminal WW domain, which is essential for protein targeting and localization. The other binding site is located in the C-terminal catalytic domain, which is structural homologous to the FK506-binding protein (FKBP) class of PPIases. A flexible linker of 12 residues connects the WW and catalytic domain. To characterize the structure and dynamics of full-length Pin1 in solution, high resolution NMR methods have been used to map the nature of interactions between the two domains of Pin1. In addition, the influence of target peptides on domain interactions has been investigated. The studies reveal a dynamic picture of the domain interactions. 15N spin relaxation data, differential chemical shift mapping, and residual dipolar coupling data indicate that Pin1 can either behave as two independent domains connected by the flexible linker or as a single intact domain with some amount of hinge bending motion depending on the sequence of the bound peptide. The functional importance of the modulation of relative domain flexibility in light of the multitude of interaction partners of Pin1 is discussed.
Author: | Doris M. Jacobs, Krishna SaxenaORCiDGND, Martin Vogtherr, Pau BernadóORCiD, Miquel PonsORCiD, Klaus M. FiebigORCiD |
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URN: | urn:nbn:de:hebis:30:3-760627 |
DOI: | https://doi.org/10.1074/jbc.M300796200 |
ISSN: | 0021-9258 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/12686540 |
Parent Title (English): | Journal of biological chemistry |
Publisher: | American Society for Biochemistry and Molecular Biology Publications |
Place of publication: | Bethesda, Md |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2021/01/04 |
Year of first Publication: | 2003 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2024/04/16 |
Volume: | 278.2003 |
Issue: | 28 |
Page Number: | 9 |
First Page: | 26174 |
Last Page: | 26182 |
Institutes: | Biochemie, Chemie und Pharmazie / Biochemie und Chemie |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - CC BY - Namensnennung 4.0 International |