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PDBsum entry 3fay
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Membrane protein
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PDB id
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3fay
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References listed in PDB file
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Key reference
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Title
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Crystal structure of the gtpase-Activating protein-Related domain from iqgap1.
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Authors
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V.B.Kurella,
J.M.Richard,
C.L.Parke,
L.F.Lecour,
H.D.Bellamy,
D.K.Worthylake.
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Ref.
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J Biol Chem, 2009,
284,
14857-14865.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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IQGAP1 is a 190-kDa molecular scaffold containing several domains required for
interaction with numerous proteins. One domain is homologous to Ras
GTPase-activating protein (GAP) domains. However, instead of accelerating
hydrolysis of bound GTP on Ras IQGAP1, using its GAP-related domain (GRD) binds
to Cdc42 and Rac1 and stabilizes their GTP-bound states. We report here the
crystal structure of the isolated IQGAP1 GRD. Despite low sequence conservation,
the overall structure of the GRD is very similar to the GAP domains from p120
RasGAP, neurofibromin, and SynGAP. However, instead of the catalytic "arginine
finger" seen in functional Ras GAPs, the GRD has a conserved threonine residue.
GRD residues 1099-1129 have no structural equivalent in RasGAP and are seen to
form an extension at one end of the molecule. Because the sequence of these
residues is highly conserved, this region likely confers a functionality
particular to IQGAP family GRDs. We have used isothermal titration calorimetry
to demonstrate that the isolated GRD binds to active Cdc42. Assuming a mode of
interaction similar to that displayed in the Ras-RasGAP complex, we created an
energy-minimized model of Cdc42.GTP bound to the GRD. Residues of the GRD that
contact Cdc42 map to the surface of the GRD that displays the highest level of
sequence conservation. The model indicates that steric clash between threonine
1046 with the phosphate-binding loop and other subtle changes would likely
disrupt the proper geometry required for GTP hydrolysis.
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Figure 1.
Experimental electron density. Density-modified experimental
phases and λ[1] amplitudes (all |F| > 0) were used to calculate
this map in the resolution range of 25-2.4 Å. The map is
contoured at 1.4 σ. In the lower right of the picture are
Tyr^1193 and Arg^1194.
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Figure 2.
The IQGAP1 GRD and GAP-334 have very similar tertiary
structures. The GRD (left) and GAP-334 (Protein Data Bank code
1WER; right) were superimposed using combinatorial extension
(29) to align the coordinates for this figure (root mean square
deviation = 3.3 Å for 312 Cα atoms). The cartoon has been
colored orange and yellow for the Ex domains of the GRD and
GAP-334, respectively. The central domains are colored blue or
light blue, and the 31-residue insertion characteristic of IQGAP
GRDs is colored green.3[10] helices are shown in dark gray, and
a five-residue π helix containing the ^1192YYR^1194 motif in
the GRD is shown in dark blue. Thr^1046 of the GRD and Arg^789
of GAP-334 are shown as stick representations in magenta.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2009,
284,
14857-14865)
copyright 2009.
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