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Roles of Two Energetically Coupled Dynamic Processes in the Vav Guanine Nucleotide Exchange Factor
Author(s) -
Li Pilong,
Martins Ilidio R.S.,
Amarasinghe Gaya K.,
Yu BingKe,
Rosen Michael K.
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1017-d
We used NMR analysis and biochemical studies to investigate dynamics‐function relationships in the Vav proto‐oncoprotein. The guanine nucleotide exchange factor (GEF) activity of Vav’s Dbl homology (DH) domain is inhibited by a helix from an adjacent fragment. Phosphorylation of a tyrosine residue in the helix is responsible for release of autoinhibition and therefore GEF activation. NMR measurements revealed that the autoinhibited DH is in equilibrium between a ground state where the inhibitory helix binds to the GEF active site and an excited state where the helix assumes an extended conformation and the active site is exposed. Using NMR and biochemical studies, we demonstrated that thermodynamics of the helix opening and closing transition governs the rate of tyrosine phosphorylation. In addition, we discovered a second dynamic process that is intrinsic to the DH domain, and which may be involved in further regulation of GEF activity. Coexistence of the two energetically coupled processes results in a four‐state equilibrium in the autoinhibited DH domain. Ongoing efforts are devoted to parameterize the four‐state equilibrium using NMR measurements of relaxation dispersion.

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