PDBsum entry 1xa6

Signaling protein

PDB id: 1xa6

Contents

Protein chain

399 a.a. *

Metals

_ZN ×2

* Residue conservation analysis

PDB id:

1xa6

Name:

Signaling protein

Title:

Crystal structure of the human beta2-chimaerin

Structure:

Beta2-chimaerin. Chain: a. Synonym: beta-chimerin, rho-gtpase-activating protein 3. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

3.20Å R-factor: 0.252 R-free: 0.298

Authors:

B.Canagarajah,F.C.Leskow,J.Y.Ho,H.Mischak,L.F.Saidi,M.G.Kazanietz, J.H.Hurley

Key ref:

B.Canagarajah et al. (2004). Structural mechanism for lipid activation of the Rac-specific GAP, beta2-chimaerin. Cell, 119, 407-418. PubMed id: 15507211 DOI: 10.1016/j.cell.2004.10.012

Date:

25-Aug-04 Release date: 23-Nov-04

Protein chain

P52757  (CHIO_HUMAN) -  Beta-chimaerin from Homo sapiens

Seq: 468 a.a.

Struc: 399 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1016/j.cell.2004.10.012

Cell 119:407-418 (2004)

PubMed id: 15507211

Structural mechanism for lipid activation of the Rac-specific GAP, beta2-chimaerin.

B.Canagarajah, F.C.Leskow, J.Y.Ho, H.Mischak, L.F.Saidi, M.G.Kazanietz, J.H.Hurley.

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.

Selected figure(s)

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.

Figures were selected by the author.