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Demonstration of long-range interactions in a PDZ domain by NMR, kinetics, and protein engineering
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2006 (English)In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 14, no 12, 1801-1809 p.Article in journal (Refereed) Published
Abstract [en]

Understanding the basis of communication within protein domains is a major challenge in structural biology. We present structural and dynamical evidence for allosteric effects in a PDZ domain, PDZ2 from the tyrosine phosphatase PTP-BL, upon binding to a target peptide. The NMR structures of its free and peptide-bound states differ in the orientation of helix alpha 2 with respect to the remainder of the molecule, concomitant with a readjustment of the hydrophobic core. Using an ultrafast mixing instrument, we detected a deviation from simple bimolecular kinetics for the association with peptide that is consistent with a rate-limiting conformational change in the protein (k(obs) similar to 7 x 10(3) s(-1)) and an induced-fit model. Furthermore, the binding kinetics of 15 mutants revealed that binding is regulated by long-range interactions, which can be correlated with the structural rearrangements resulting from peptide binding. The homologous protein PSD-95 PDZ3 did not display a similar ligand-induced conformational change.

Place, publisher, year, edition, pages
2006. Vol. 14, no 12, 1801-1809 p.
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Medical and Health Sciences
URN: urn:nbn:se:uu:diva-22435DOI: 10.1016/j.str.2006.10.010ISI: 000242888600008PubMedID: 17161370OAI: oai:DiVA.org:uu-22435DiVA: diva2:50208
Available from: 2007-01-17 Created: 2007-01-17 Last updated: 2011-02-22Bibliographically approved

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Engström, ÅkeJemth, Per
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Department of Medical Biochemistry and Microbiology
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