TY - JOUR
T1 - Structural and Energetic Mechanisms of Cooperative Autoinhibition and Activation of Vav1
AU - Yu, Bingke
AU - Martins, Ilídio R S
AU - Li, Pilong
AU - Amarasinghe, Gaya K.
AU - Umetani, Junko
AU - Fernandez-Zapico, Martin E.
AU - Billadeau, Daniel D.
AU - Machius, Mischa
AU - Tomchick, Diana R.
AU - Rosen, Michael K.
N1 - Funding Information:
We thank Carlos Amezcua and Chad Brautigam for technical assistance, Lewis Kay for providing NMR pulse sequences, Shae Padrick and Rama Ranganathan for discussion, and Yuh Min Chook for critical reading of the manuscript. I.R.S.M. was supported by fellowships from the Foundation for Science and Technology (Portugal) and the Luso-American Development Foundation (Portugal). G.K.A. was supported by a postdoctoral fellowship from the Cancer Research Institute. This work was supported by NIH grants GM066930 to M.K.R., AI065474 and CA102721 to D.D.B., and CA102721 and CA136526 to M.E.F. and by the Howard Hughes Medical Institute. D.D.B. is a Leukemia and Lymphoma Society Scholar. Use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Energy Research, under Contract No. W-31-109-ENG-38.
PY - 2010/1/22
Y1 - 2010/1/22
N2 - Vav proteins are guanine nucleotide exchange factors (GEFs) for Rho family GTPases. They control processes including T cell activation, phagocytosis, and migration of normal and transformed cells. We report the structure and biophysical and cellular analyses of the five-domain autoinhibitory element of Vav1. The catalytic Dbl homology (DH) domain of Vav1 is controlled by two energetically coupled processes. The DH active site is directly, but weakly, inhibited by a helix from the adjacent Acidic domain. This core interaction is strengthened 10-fold by contacts of the calponin homology (CH) domain with the Acidic, pleckstrin homology, and DH domains. This construction enables efficient, stepwise relief of autoinhibition: initial phosphorylation events disrupt the modulatory CH contacts, facilitating phosphorylation of the inhibitory helix and consequent GEF activation. Our findings illustrate how the opposing requirements of strong suppression of activity and rapid kinetics of activation can be achieved in multidomain systems.
AB - Vav proteins are guanine nucleotide exchange factors (GEFs) for Rho family GTPases. They control processes including T cell activation, phagocytosis, and migration of normal and transformed cells. We report the structure and biophysical and cellular analyses of the five-domain autoinhibitory element of Vav1. The catalytic Dbl homology (DH) domain of Vav1 is controlled by two energetically coupled processes. The DH active site is directly, but weakly, inhibited by a helix from the adjacent Acidic domain. This core interaction is strengthened 10-fold by contacts of the calponin homology (CH) domain with the Acidic, pleckstrin homology, and DH domains. This construction enables efficient, stepwise relief of autoinhibition: initial phosphorylation events disrupt the modulatory CH contacts, facilitating phosphorylation of the inhibitory helix and consequent GEF activation. Our findings illustrate how the opposing requirements of strong suppression of activity and rapid kinetics of activation can be achieved in multidomain systems.
KW - SIGNALING
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U2 - 10.1016/j.cell.2009.12.033
DO - 10.1016/j.cell.2009.12.033
M3 - Article
C2 - 20141838
AN - SCOPUS:74549174000
SN - 0092-8674
VL - 140
SP - 246
EP - 256
JO - Cell
JF - Cell
IS - 2
ER -