Transient helical structure during PI3K and Fyn SH3 domain folding

Yoshitaka Matsumura, Masaji Shinjo, Seung Joong Kim, Nobuyuki Okishio, Martin Gruebele, Hiroshi Kihara

Research output: Contribution to journalArticlepeer-review


A growing list of proteins, including the β-sheet-rich SH3 domain, is known to transiently populate a compact α-helical intermediate before settling into the native structure. Examples have been discovered in cryogenic solvent as well as by pressure jumps. Earlier studies of λ repressor mutants showed that transient states with excess helix are robust in an all-α protein. Here we extend a previous study of src SH3 domain to two new SH3 sequences, phosphatidylinositol 3-kinase (PI3K) and a Fyn mutant, to see how robust such helix-rich transients are to sequence variations in this β-sheet fold. We quantify helical structure by circular dichroism (CD), protein compactness by small-angle X-ray scattering (SAXS), and transient helical populations by cryo-stopped-flow CD. Our results show that transient compact helix-rich intermediates are easily accessible on the folding landscape of different SH3 domains. In molecular dynamics simulations, force field errors are often blamed for transient non-native structure. We suggest that experimental examples of very fast α-rich transient misfolding could become a more subtle test for further force field improvements than observation of the native state alone.

Original languageEnglish (US)
Pages (from-to)4836-4843
Number of pages8
JournalJournal of Physical Chemistry B
Issue number17
StatePublished - May 2 2013

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry


Dive into the research topics of 'Transient helical structure during PI3K and Fyn SH3 domain folding'. Together they form a unique fingerprint.

Cite this