 |
PDBsum entry 1xa6
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Signaling protein
|
PDB id
|
|
|
|
1xa6
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural mechanism for lipid activation of the rac-Specific gap, Beta2-Chimaerin.
|
|
|
Authors
|
|
B.Canagarajah,
F.C.Leskow,
J.Y.Ho,
H.Mischak,
L.F.Saidi,
M.G.Kazanietz,
J.H.Hurley.
|
|
|
Ref.
|
|
Cell, 2004,
119,
407-418.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The lipid second messenger diacylglycerol acts by binding to the C1 domains of
target proteins, which translocate to cell membranes and are allosterically
activated. Here we report the crystal structure at 3.2 A resolution of one such
protein, beta2-chimaerin, a GTPase-activating protein for the small GTPase Rac,
in its inactive conformation. The structure shows that in the inactive state,
the N terminus of beta2-chimaerin protrudes into the active site of the RacGAP
domain, sterically blocking Rac binding. The diacylglycerol and phospholipid
membrane binding site on the C1 domain is buried by contacts with the four
different regions of beta2-chimaerin: the N terminus, SH2 domain, RacGAP domain,
and the linker between the SH2 and C1 domains. Phospholipid binding to the C1
domain triggers the cooperative dissociation of these interactions, allowing the
N terminus to move out of the active site and thereby activating the enzyme.
|
|
|
|
|
|
|
|
Figure 1.
Figure 1. Structure of β2-Chimaerin(A) Refined model of
β2-chimaerin in the vicinity of Gln32 superimposed on the
solvent-modified single anomalous dispersion (SAD) Fourier
synthesis.(B) Overall structure of β2-chimaerin. The domains
red (SH2), blue (C1), green (RacGAP), and grey (linkers).(C)
Structure of the SH2 domain (red) overlaid on the SH2 domain of
Src (cyan) and showing the internal phosphotyrosine-containing
sequence in Src in a stick representation.(D) Structure of the
C1 domain (blue) overlaid on the C1B domain of PKCδ (cyan) and
showing phorbol ester as bound to the the PKCδ-C1B.(E)
Structure of the RacGAP domain (green) overlaid on the RhoGAP
domain of p50RhoGAP (grey), showing the bound Cdc42 protein
(yellow) in complex with GDP and AlF[x]^− (stick model).(F)
Linker regions are shown in a worm represenation, with the rest
of β2-chimaerin shown in a space-filling representation,
oriented and colored as in (B).
|
|
Figure 7.
Figure 7. Autoinhibition and Activation of the RacGAP
Domain(A) Pro21 and Pro22 (yellow stick model) of β2-chimaerin,
overlaid on the docked structure of Rac (translucent surface and
model).(B) The αF′ helix in the observed conformation (green)
and predicted active conformation (cyan and translucent), with
the N-terminal region in gray.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Cell Press:
Cell
(2004,
119,
407-418)
copyright 2004.
|
|
|
|
|
|
|
