Document Detail

Transient helical structure during PI3K and Fyn SH3 domain folding.
MedLine Citation:
PMID:  23537292     Owner:  NLM     Status:  MEDLINE    
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.
Yoshitaka Matsumura; Masaji Shinjo; Seung Joong Kim; Nobuyuki Okishio; Martin Gruebele; Hiroshi Kihara
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-04-18
Journal Detail:
Title:  The journal of physical chemistry. B     Volume:  117     ISSN:  1520-5207     ISO Abbreviation:  J Phys Chem B     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-05-02     Completed Date:  2013-11-26     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  101157530     Medline TA:  J Phys Chem B     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4836-43     Citation Subset:  IM    
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MeSH Terms
Amino Acid Sequence
Circular Dichroism
Guanidine / chemistry
Molecular Dynamics Simulation
Molecular Sequence Data
Phosphatidylinositol 3-Kinases / chemistry*,  metabolism
Protein Refolding
Protein Structure, Secondary
Proto-Oncogene Proteins c-fyn / chemistry*,  metabolism
Scattering, Small Angle
Sequence Alignment
X-Ray Diffraction
src Homology Domains
Grant Support
2 P41 RR008630-17/RR/NCRR NIH HHS; 9 P41 GM103622-17/GM/NIGMS NIH HHS; R01 GM093318/GM/NIGMS NIH HHS; R01-GM093318/GM/NIGMS NIH HHS
Reg. No./Substance:
EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC protein, human; EC Proteins c-fyn; JU58VJ6Y3B/Guanidine
Erratum In:
J Phys Chem B. 2013 Dec 5;117(48):15233

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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