 |
PDBsum entry 3ky9
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Structural and energetic mechanisms of cooperative autoinhibition and activation of vav1.
|
|
|
Authors
|
|
B.Yu,
I.R.Martins,
P.Li,
G.K.Amarasinghe,
J.Umetani,
M.E.Fernandez-Zapico,
D.D.Billadeau,
M.Machius,
D.R.Tomchick,
M.K.Rosen.
|
|
|
Ref.
|
|
Cell, 2010,
140,
246-256.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
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.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
Internal dynamics control activation and activity of the autoinhibited vav dh domain.
|
|
|
Authors
|
|
P.Li,
I.R.Martins,
G.K.Amarasinghe,
M.K.Rosen.
|
|
|
Ref.
|
|
Nat Struct Biol, 2008,
15,
613-618.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #2
|
|
|
Title
|
|
Acidic region tyrosines provide access points for allosteric activation of the autoinhibited vav1 dbl homology domain.
|
|
|
Authors
|
|
G.K.Amarasinghe,
M.K.Rosen.
|
|
|
Ref.
|
|
Biochemistry, 2005,
44,
15257-15268.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #3
|
|
|
Title
|
|
Structural basis for relief of autoinhibition of the dbl homology domain of proto-Oncogene vav by tyrosine phosphorylation.
|
|
|
Authors
|
|
B.Aghazadeh,
W.E.Lowry,
X.Y.Huang,
M.K.Rosen.
|
|
|
Ref.
|
|
Cell, 2000,
102,
625-633.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Figure 3.
Figure 3. Structure of the Autoinhibited Vav170–375(A)
Ribbons ([12]) depiction of a representative confomer from the
final ensemble of Vav DH domain structures. Residues 170–180
encompassing the inhibitory helix are red, 181–375 are yellow,
loops are green.(B) Autoinhibited DH domain, rotated  vert,
similar 90° about a vertical axis with respect to 3A. Left:
a yellow molecular surface of the DH domain (residues 195–375)
with the N-terminal autoinhibitory arm (residues 170–194)
depicted as a red ribbon. Right: indicated expansion of the
binding site of the inhibitory helix on the DH domain. Residues
involved in the interaction are colored green on the DH domain
and red on the inhibitory helix. Molecular surfaces of the DH
domain represented as a yellow net. Figure produced with GRASP
([45]).
|
|
Figure 5.
Figure 5. Model of Vav DH Domain Autoinhibition by Tyr174
Src Recognition Motif and PH Domain
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
with permission from Cell Press
|
|
|
|
|
|
|
