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An expanded view of the protein folding landscape of PDZ domains
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Per Jemth)
University of Copenhagen. (Department of Drug Design and Pharmacology)
University of Copenhagen. (Department of Drug Design and Pharmacology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. ETH. (Chi Celstine)
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2012 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 421, no 3, 550-553 p.Article in journal (Refereed) Published
Abstract [en]

Most protein domains fold in an apparently co-operative and two-state manner with only the native and denatured states significantly populated at any experimental condition. However, the protein folding energy landscape is often rugged and different transition states may be rate limiting for the folding reaction under different conditions, as seen for the PDZ protein domain family. We have here analyzed the folding kinetics of two PDZ domains and found that a previously undetected third transition state is rate limiting under conditions that stabilize the native state relative to the denatured state. In light of these results, we have re-analyzed previous folding data on PDZ domains and present a unified folding mechanism with three distinct transition states separated by two high-energy intermediates. Our data show that sequence composition tunes the relative stabilities of folding transition states within the PDZ family, while the overall mechanism is determined by topology. This model captures the kinetic folding mechanism of all PDZ domains studied to date.

Place, publisher, year, edition, pages
2012. Vol. 421, no 3, 550-553 p.
Keyword [en]
PDZ folding transition state
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-185575DOI: 10.1016/j.bbrc.2012.04.042ISI: 000306152000025PubMedID: 22521641OAI: oai:DiVA.org:uu-185575DiVA: diva2:572158
Available from: 2012-11-26 Created: 2012-11-26 Last updated: 2017-10-16Bibliographically approved
In thesis
1. Protein Folding, Binding and Evolution: PDZ domains and paralemmins as model systems
Open this publication in new window or tab >>Protein Folding, Binding and Evolution: PDZ domains and paralemmins as model systems
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins present at the synapse need to be multitasking in order to perform all vital functions in this limited space. In this thesis I have analyzed the function and evolution of such proteins, focusing on the PDZ domain and the paralemmin family. The PDZ domains bind to a wide variety of interaction partners. The affinity for each partner is regulated by residues at the binding site, but also through intradomain allostery. How this intradomain allostery is transferred to the binding site is not established. I here show that side chain interactions can explain all transfer of intradomain allostery in three analyzed PDZ domains. A circularly permuted PDZ domain has an identical set of amino acids as the original protein and a very similar structure with only a few perturbed side chains. By using the circular permutant I show that a slight alteration in the position of a side chain leads to a corresponding change in allosteric signal. I further study the folding of several PDZ domains and show that they all fold via a conserved folding mechanism, supporting the notion that the final structure has a part in deciding folding mechanism. The folding mechanism of the circularly permuted PDZ domain is conserved compared to the original protein illustrating how circular permutations can be tolerated through evolution. The multifunctionality of paralemmins probably lies in their highly flexible structures. I have studied the evolution of the paralemmins and found that the four mammalian paralemmins arose in the two whole-genome duplications that occurred early in the vertebrate evolution. The fact that all four paralemmins have survived evolution since the gene duplications suggests that they have important functions, possibly in the development of the nervous system. Synaptic proteins are crucial for many biological processes, and their misfolding implicated in many diseases. The results presented here shed light on the mechanisms of action of the synaptic proteins and will help us to understand how they generate disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 47 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1006
Keyword
Protein folding, evolution, binding, allostery, Paralemmin, PDZ domain
National Category
Biochemistry and Molecular Biology Structural Biology Genetics
Identifiers
urn:nbn:se:uu:diva-185573 (URN)978-91-554-8563-4 (ISBN)
Public defence
2013-02-01, B42, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2013-01-11 Created: 2012-11-26 Last updated: 2013-02-11Bibliographically approved

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