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PDBsum entry 2bap
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Signaling protein
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PDB id
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2bap
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References listed in PDB file
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Key reference
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Title
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The regulation of mdia1 by autoinhibition and its release by rhoGtp.
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Authors
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M.Lammers,
R.Rose,
A.Scrima,
A.Wittinghofer.
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Ref.
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Embo J, 2005,
24,
4176-4187.
[DOI no: ]
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PubMed id
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Abstract
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Formins induce the nucleation and polymerisation of unbranched actin filaments
via the formin-homology domains 1 and 2. Diaphanous-related formins (Drfs) are
regulated by a RhoGTPase-binding domain situated in the amino-terminal
(N-terminal) region and a carboxy-terminal Diaphanous-autoregulatory domain
(DAD), whose interaction stabilises an autoinhibited inactive conformation.
Binding of active Rho releases DAD and activates the catalytic activity of mDia.
Here, we report on the interaction of DAD with the regulatory N-terminus of
mDia1 (mDia(N)) and its release by Rho*GTP. We have defined the elements
required for tight binding and solved the three-dimensional structure of a
complex between an mDia(N) construct and DAD by X-ray crystallography. The core
DAD region is an alpha-helical peptide, which binds in the most highly conserved
region of mDia(N) using mainly hydrophobic interactions. The structure suggests
a two-step mechanism for release of autoinhibition whereby Rho*GTP, although
having a partially nonoverlapping binding site, displaces DAD by ionic repulsion
and steric clashes. We show that Rho*GTP accelerates the dissociation of DAD
from the mDia(N)*DAD complex.
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Figure 5.
Figure 5 Structural model for release of DAD by Rho binding. (A)
Model of a complex of mDia[N] with Rho  GTP
and the DCR, using the previous RhoC complex structure (Rose et
al, 2005b) and the DAD complex structure obtained here and the
superimposition shown in Figure 4B. (B) Details of the
electrostatic repulsion between DAD and Rho in a proposed
ternary mDia[N]-Rho-DAD complex; the steric clash on inserting
the next DAD residue, Thr1179, is indicated by a green circle.
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Figure 7.
Figure 7 Schematic two-step-binding model of DAD release from
the regulatory region of mDia1 by Rho GTP,
as described in the text.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Embo J
(2005,
24,
4176-4187)
copyright 2005.
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