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Common motifs and topological effects in the protein folding transition state.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. (Mikael Oliveberg)
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2006 (English)In: Journal of Molecular Biology, ISSN 0022-2836, ISSN 0022-2836, Vol. 359, no 4, 1075-1085 p.Article in journal (Refereed) Published
Abstract [en]

Through extensive experiment, simulation, and analysis of protein S6 (IRIS), we find that variations in nucleation and folding pathway between circular permutations are determined principally by the restraints of topology and specific nucleation, and affected by changes in chain entropy. Simulations also relate topological features to experimentally measured stabilities. Despite many sizable changes in Φ values and the structure of the transition state ensemble that result from permutation, we observe a common theme: the critical nucleus in each of the mutants share a subset of residues that can be mapped to the critical nucleus residues of the wild-type. Circular permutations create new N and C termini, which are the location of the largest disruption of the folding nucleus, leading to a decrease in both Φ values and the role in nucleation. Mutant nuclei are built around the wild-type nucleus but are biased towards different parts of the S6 structure depending on the topological and entropic changes induced by the location of the new N and C termini.

Place, publisher, year, edition, pages
2006. Vol. 359, no 4, 1075-1085 p.
Keyword [en]
ensemble, simulatoin, circular permutation, protein S6
URN: urn:nbn:se:su:diva-29977DOI: 10.1016/j.jmb.2006.04.015OAI: diva2:236865
Available from: 2009-09-25 Created: 2009-09-25 Last updated: 2009-09-25Bibliographically approved
In thesis
1. Folding of the Ribosomal protein S6: The role of sequence connectivity, overlapping foldons, and parallel pathways
Open this publication in new window or tab >>Folding of the Ribosomal protein S6: The role of sequence connectivity, overlapping foldons, and parallel pathways
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

To investigate how protein folding is affected by sequence connectivity five topological variants of the ribosomal protein S6 were constructed through circular permutation.  In these constructs, the chain connectivity (i.e. the order of secondary-structure elements) is changed without changing the native-state topology.  The effects of the permutations on the folding process were then characterised by φ-value analysis, which estimates the extent of contact formations in the transition-state ensemble.  The results show that the folding nuclei of the wild-type and permutant proteins comprises a common motif of one α-helix docking against two β-sheets, i.e. the minimal structure for folding.  However, this motif is recruited in different parts of the S6 structure depending on the permutation, either in the α1 or α2 half of the protein.  This minimal structure is not unique for S6 but can also be seen in other proteins.  As an effect of the dual nucleation possibilities, the transition-state changes describe a competition between two parallel pathways, which both include the central β-stand 1.  This strand constitutes thus a structural overlap between the two competing nuclei.  As similar overlap between competing nuclei is also seen in other proteins, I hypothesise that the coupling of several small nuclei into extended ‘super nuclei’ represents a general principle for propagating folding cooperativity across large structural distances.  Moreover, I demonstrate by NMR analysis that the existence of multiple folding nuclei renders the H/D-exchange kinetics independent of the folding pathway.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2009. 94 p.
protein folding, protein stability, two-state folding, S6, chevron plot, transition state, parallell pathways, foldon, two-channel landscape, protein engineering, H/D-exchange
National Category
Biochemistry and Molecular Biology
Research subject
urn:nbn:se:su:diva-29963 (URN)978-91-7155-939-5 (ISBN)
Public defence
2009-10-24, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper IV: ManuscriptAvailable from: 2009-10-01 Created: 2009-09-23 Last updated: 2009-09-29Bibliographically approved

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