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PDBsum entry 1ki1
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Signaling protein
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PDB id
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1ki1
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural basis for the selective activation of rho gtpases by dbl exchange factors.
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Authors
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J.T.Snyder,
D.K.Worthylake,
K.L.Rossman,
L.Betts,
W.M.Pruitt,
D.P.Siderovski,
C.J.Der,
J.Sondek.
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Ref.
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Nat Struct Biol, 2002,
9,
468-475.
[DOI no: ]
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PubMed id
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Abstract
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Activation of Rho-family GTPases involves the removal of bound GDP and the
subsequent loading of GTP, all catalyzed by guanine nucleotide exchange factors
(GEFs) of the Dbl-family. Despite high sequence conservation among Rho GTPases,
Dbl proteins possess a wide spectrum of discriminatory potentials for Rho-family
members. To rationalize this specificity, we have determined crystal structures
of the conserved, catalytic fragments (Dbl and pleckstrin homology domains) of
the exchange factors intersectin and Dbs in complex with their cognate GTPases,
Cdc42 and RhoA, respectively. Structure-based mutagenesis of intersectin and Dbs
reveals the key determinants responsible for promoting exchange activity in
Cdc42, Rac1 and RhoA. These findings provide critical insight into the
structural features necessary for the proper pairing of Dbl-exchange factors
with Rho GTPases and now allow for the detailed manipulation of signaling
pathways mediated by these oncoproteins in vivo.
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Figure 1.
Figure 1. Overall structures of ITSN -Cdc42 and Dbs -RhoA. a,
Stereo view of an electron density map calculated using
density-modified MAD experimental phases contoured at 1.2  and
displayed with the refined  6
helix of the DH domain of ITSN. b, Stereo view of a
representative portion of the 2F[o]-F[c] electron density of the
Dbs -RhoA structure, contoured at 1.3 and
displayed with residues 759 -772 of Dbs (yellow) and residues 54
-62 of RhoA (green). c, Ribbon diagram of the ITSN -Cdc42
structure. The DH domain is yellow, and the PH domain is blue,
with defined secondary structural elements labeled in accordance
with described nomenclature^8. Cdc42 is green, except for the
switch regions (s1 = residues 26 -40 and s2 = residues 57 -76),
which are red. d, Ribbon diagram of the Dbs -RhoA complex.
Coloring and labeling are equivalent to the ITSN -Cdc42
structure. All figures were prepared using SPOCK
(http://quorum.tamu.edu/jon/spock/) or MOLSCRIPT36.
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Figure 5.
Figure 5. Comparison of the Dbs -RhoA, Dbs -Cdc42 and Tiam1
-Rac1 structures. a, Interface of the DH domain of Dbs
(yellow) and Cdc42 (green). b, Interface of the DH domain of Dbs
and RhoA (green). c, Superposition of the backbone traces of the
4/
5
loop of ITSN and Tiam1 on the Dbs -RhoA complex. ITSN (blue) and
Tiam1 (red) backbones are semitransparent, and Dbs is yellow. d,
Interface of the DH domain of Tiam1 (yellow) and Rac1 (green).
Unless otherwise noted, coloring is according to the styles used
in Fig. 3.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2002,
9,
468-475)
copyright 2002.
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