Tuning protein autoinhibition by domain destabilization

Jae Hyun Cho, Vasant Muralidharan, Miquel Vila-Perello, Daniel P. Raleigh, Tom W. Muir, Arthur G. Palmer

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Activation of many multidomain signaling proteins requires rearrangement of autoinhibitory interdomain interactions that occlude activator binding sites. In one model for activation, the major inactive conformation exists in equilibrium with activated-like conformations that can be stabilized by ligand binding or post-translational modifications. We established the molecular basis for this model for the archetypal signaling adaptor protein Crk-II by measuring the thermodynamics and kinetics of the equilibrium between autoinhibited and activated-like states. We used fluorescence and NMR spectroscopies together with segmental isotopic labeling by means of expressed protein ligation. The results demonstrate that intramolecular domain-domain interactions both stabilize the autoinhibited state and induce the activated-like conformation. A combination of favorable interdomain interactions and unfavorable intradomain structural changes fine-tunes the population of the activated-like conformation and allows facile response to activators. This mechanism suggests a general strategy for optimization of autoinhibitory interactions of multidomain proteins.

Original languageEnglish (US)
Pages (from-to)550-555
Number of pages6
JournalNature Structural and Molecular Biology
Volume18
Issue number5
DOIs
StatePublished - May 2011

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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    Cho, J. H., Muralidharan, V., Vila-Perello, M., Raleigh, D. P., Muir, T. W., & Palmer, A. G. (2011). Tuning protein autoinhibition by domain destabilization. Nature Structural and Molecular Biology, 18(5), 550-555. https://doi.org/10.1038/nsmb.2039