Tolerance of Protein Folding to a Circular Permutation in a PDZ Domain

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 structu...

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Main Authors:	Hultqvist, Greta, Punekar, Avinash S., Morrone, Angela, Chi, Celestine N., Engström, Åke, Selmer, Maria, Gianni, Stefano, Jemth, Per
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503759/

id	pubmed-3503759
recordtype	oai_dc
spelling	pubmed-35037592012-11-26 Tolerance of Protein Folding to a Circular Permutation in a PDZ Domain Hultqvist, Greta Punekar, Avinash S. Morrone, Angela Chi, Celestine N. Engström, Åke Selmer, Maria Gianni, Stefano Jemth, Per Research Article 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. Public Library of Science 2012-11-21 /pmc/articles/PMC3503759/ /pubmed/23185531 http://dx.doi.org/10.1371/journal.pone.0050055 Text en © 2012 Hultqvist et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Hultqvist, Greta Punekar, Avinash S. Morrone, Angela Chi, Celestine N. Engström, Åke Selmer, Maria Gianni, Stefano Jemth, Per
spellingShingle	Hultqvist, Greta Punekar, Avinash S. Morrone, Angela Chi, Celestine N. Engström, Åke Selmer, Maria Gianni, Stefano Jemth, Per Tolerance of Protein Folding to a Circular Permutation in a PDZ Domain
author_facet	Hultqvist, Greta Punekar, Avinash S. Morrone, Angela Chi, Celestine N. Engström, Åke Selmer, Maria Gianni, Stefano Jemth, Per
author_sort	Hultqvist, Greta
title	Tolerance of Protein Folding to a Circular Permutation in a PDZ Domain
title_short	Tolerance of Protein Folding to a Circular Permutation in a PDZ Domain
title_full	Tolerance of Protein Folding to a Circular Permutation in a PDZ Domain
title_fullStr	Tolerance of Protein Folding to a Circular Permutation in a PDZ Domain
title_full_unstemmed	Tolerance of Protein Folding to a Circular Permutation in a PDZ Domain
title_sort	tolerance of protein folding to a circular permutation in a pdz domain
description	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.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503759/
_version_	1611934380495732736

Tolerance of Protein Folding to a Circular Permutation in a PDZ Domain

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