Obligatory steps in protein folding and the conformational diversity of the transition state

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • J C Martinez - , European Molecular Biology Laboratory (EMBL) Heidelberg, Structures & Biocomputing, University of Granada (Author)
  • M T Pisabarro - , Structural Bioinformatics (Research Group), Biotechnology Center, European Molecular Biology Laboratory (EMBL) Heidelberg, Structures & Biocomputing (Author)
  • L Serrano - , European Molecular Biology Laboratory (EMBL) Heidelberg, Structures & Biocomputing (Author)

Abstract

We have analyzed the existence of obligatory steps in the folding reaction of the alpha-spectrin SH3 domain by mutating Asp 48 (D48G), which is at position i+3 of an isolated two-residue type II' beta-turn. Calorimetry and X-ray analysis show an entropic stabilizing effect resulting from local changes at the dihedral angles of the beta-turn. Kinetic analysis of D48G shows that this beta-turn is fully formed in the transition state, while there is no evidence of its formation in an isolated fragment. Introduction of several mutations in the D48G protein reveals that the local stabilization has not significantly altered the transition state ensemble. All these results, together with previous analysis of other alpha-spectrin and src SH3 mutants, indicate that: (i) in the folding reaction there could be obligatory steps which are not necessarily part of the folding nucleus; (ii) transition state ensembles in beta-sheet proteins could be quite defined and conformationally restricted ('mechanic folding nucleus'); and (iii) transition state ensembles in some proteins could be evolutionarily conserved.

Details

Original languageEnglish
Pages (from-to)721-729
Number of pages9
JournalNature Structural Biology
Volume5
Issue number8
Publication statusPublished - Aug 1998
Peer-reviewedYes

External IDs

Scopus 0031825181

Keywords

Keywords

  • Amino Acid Sequence, Aspartic Acid/genetics, Calorimetry, Differential Scanning, Crystallography, X-Ray, DNA Mutational Analysis, Kinetics, Models, Chemical, Models, Molecular, Molecular Sequence Data, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, Protein Folding, Spectrin/chemistry, src Homology Domains

Library keywords