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Tolerance of Protein Folding to a Circular Permutation in a PDZ Domain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Sapienza Università di Roma.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. ETH. (Chi Celestine)
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, e50055- p.Article in journal (Refereed) Published
Abstract [en]

Circular permutation is a common molecular mechanism for evolution of proteins. However, such re-arrangement of secondary structure connectivity may interfere with the folding mechanism causing accumulation of folding intermediates, which in turn can lead to misfolding. We solved the crystal structure and investigated the folding pathway of a circularly permuted variant of a PDZ domain, SAP97 PDZ2. Our data illustrate how well circular permutation may work as a mechanism for molecular evolution. The circular permutant retains the overall structure and function of the native protein domain. Further, unlike most examples in the literature, this circular permutant displays a folding mechanism that is virtually identical to that of the wild type. This observation contrasts with previous data on the circularly permuted PDZ2 domain from PTP-BL, for which the folding pathway was remarkably affected by the same mutation in sequence connectivity. The different effects of this circular permutation in two homologous proteins show the strong influence of sequence as compared to topology. Circular permutation, when peripheral to the major folding nucleus, may have little effect on folding pathways and could explain why, despite the dramatic change in primary structure, it is frequently tolerated by different protein folds.

Place, publisher, year, edition, pages
2012. Vol. 7, no 11, e50055- p.
Keyword [en]
Circular permutant, protein folding, PDZ domain
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-185577DOI: 10.1371/journal.pone.0050055ISI: 000311821000173OAI: oai:DiVA.org:uu-185577DiVA: diva2:572159
Available from: 2012-11-26 Created: 2012-11-26 Last updated: 2017-12-07Bibliographically 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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Hultqvist, GretaPunekar, AvinashChi, CelestineEngström, ÅkeSelmer, MariaJemth, Per
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