Internal dynamics control activation and activity of the autoinhibited Vav DH domain

Pilong Li, Ilídio R S Martins, Gaya K. Amarasinghe, Michael K. Rosen

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Protein motions are important to activity, but quantitative relationships between internal dynamics and function are not well understood. The Dbl homology (DH) domain of the proto-oncoprotein and guanine nucleotide exchange factor Vav1 is autoinhibited through interactions between its catalytic surface and a helix from an N-terminal acidic region. Phosphorylation of the helix relieves autoinhibition. Here we show by NMR spectroscopy that the autoinhibited DH domain exists in equilibrium between a ground state, where the active site is blocked by the inhibitory helix, and an excited state, where the helix is dissociated. Across a series of mutants that differentially sample these states, catalytic activity of the autoinhibited protein and its rate of phosphorylation are linearly dependent on the population of the excited state. Thus, internal dynamics are required for and control both basal activity and the rate of full activation of the autoinhibited DH domain.

Original languageEnglish (US)
Pages (from-to)613-618
Number of pages6
JournalNature Structural and Molecular Biology
Volume15
Issue number6
DOIs
StatePublished - Jun 2008

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Phosphorylation
Guanine Nucleotide Exchange Factors
Oncogene Proteins
Catalytic Domain
Proteins
Magnetic Resonance Spectroscopy
Population

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Internal dynamics control activation and activity of the autoinhibited Vav DH domain. / Li, Pilong; Martins, Ilídio R S; Amarasinghe, Gaya K.; Rosen, Michael K.

In: Nature Structural and Molecular Biology, Vol. 15, No. 6, 06.2008, p. 613-618.

Research output: Contribution to journalArticle

Li, Pilong ; Martins, Ilídio R S ; Amarasinghe, Gaya K. ; Rosen, Michael K. / Internal dynamics control activation and activity of the autoinhibited Vav DH domain. In: Nature Structural and Molecular Biology. 2008 ; Vol. 15, No. 6. pp. 613-618.
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