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PEDS Advance Access originally published online on January 5, 2008
Protein Engineering Design and Selection 2008 21(3):155-160; doi:10.1093/protein/gzm077
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

The folding pathway of an engineered circularly permuted PDZ domain

Ylva Ivarsson, Carlo Travaglini-Allocatelli, Veronica Morea, Maurizio Brunori and Stefano Gianni1

Istituto di Biologia e Patologia Molecolari del CNR, Dipartimento di Scienze Biochimiche ‘A. Rossi Fanelli’, Sapienza - Università di Roma ‘ La Sapienza’, Piazzale A. Moro 5, 00185 Rome, Italy

1 To whom correspondence should be addressed. E-mail: stefano.gianni{at}uniroma1.it

To understand the role of sequence connectivity in the folding pathway of a multi-state protein, we have analysed the folding kinetics of an engineered circularly permuted PDZ domain. This variant has been designed with the specific aim of posing two of the strands participating in the stabilisation of an early folding nucleus as contiguous elements in the primary structure. Folding of the circularly permuted PDZ2 has been explored by a variety of different experimental approaches including stopped-flow and continuous-flow kinetics, as well as ligand-induced folding experiments. Data reveal that although circular permutation introduces a significant destabilisation of the native state, a folding intermediate is stabilised and accumulated prior folding. Furthermore, quantitative analysis of the observed kinetics indicates an acceleration of the early folding events by more than two orders of magnitude. The results support the importance of sequence connectivity both in the mechanism and the speed of protein folding.

Keywords: circular permutation/intermediates/kinetics/protein folding/transition state

Received November 19, 2007; revised November 19, 2007; accepted November 19, 2007.


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