Crystal structure of Rac1 bound to its effector phospholipase C-beta2

• Published in: Nature structural & molecular biology Vol. 13; no. 12; pp. 1135 - 1140
• Main Authors: Jezyk, Mark R, Snyder, Jason T, Gershberg, Svetlana, Worthylake, David K, Harden, T Kendall, Sondek, John
• Format: Journal Article
• Language: English
• Published: United States 01.12.2006
• Subjects: Crystallography, X-Ray; Humans; Isoenzymes - chemistry; Isoenzymes - genetics; Isoenzymes - metabolism; Models, Molecular; Mutation - genetics; Phospholipase C beta; Protein Binding; Protein Structure, Quaternary; rac1 GTP-Binding Protein - chemistry; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Static Electricity; Type C Phospholipases - chemistry; Type C Phospholipases - genetics; Type C Phospholipases - metabolism
• ISSN: 1545-9993

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.