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Title
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Internal dynamics control activation and activity of the autoinhibited Vav DH domain.
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Authors
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P.Li,
I.R.Martins,
G.K.Amarasinghe,
M.K.Rosen.
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Ref.
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Nat Struct Biol, 2008,
15,
613-618.
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PubMed id
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Abstract
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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.
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