Crystal structure of Rac1 bound to its effector phospholipase C-beta2.
Although diverse signaling cascades require the coordinated regulation of heterotrimeric G proteins and small GTPases, these connections remain poorly understood. We present the crystal structure of the GTPase Rac1 bound to phospholipase C-beta2 (PLC-beta2), a classic effector of heterotrimeric G proteins. Rac1 engages the pleckstrin-homology (PH) domain of PLC-beta2 to optimize its orientation for substrate membranes. Gbetagamma also engages the PH domain to activate PLC-beta2, and these two activation events are compatible, leading to additive stimulation of phospholipase activity. In contrast to PLC-delta, the PH domain of PLC-beta2 cannot bind phosphoinositides, eliminating this mode of regulation. The structure of the Rac1-PLC-beta2 complex reveals determinants that dictate selectivity of PLC-beta isozymes for Rac GTPases over other Rho-family GTPases, and substitutions within PLC-beta2 abrogate its stimulation by Rac1 but not by Gbetagamma, allowing for functional dissection of this integral signaling node.
Jezyk
Mark R
MR
Department of Biochemistry and Biophysics The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
Snyder
Jason T
JT
Gershberg
Svetlana
S
Worthylake
David K
DK
Harden
T Kendall
TK
Sondek
John
J
D018360:Crystallography, X-Ray; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D054799:Phospholipase C beta; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D055672:Static Electricity; D010738:Type C Phospholipases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D007527:Isoenzymes; D010738:Type C Phospholipases; C518036:PLCB2 protein, human; D054799:Phospholipase C beta; D020830:rac1 GTP-Binding Protein