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

Author

Jezyk MR, Snyder JT, Gershberg S, Worthylake DK, Harden TK, and Sondek J

Subjects
Crystallography, X-Ray, Humans, Isoenzymes genetics, Models, Molecular, Mutation genetics, Phospholipase C beta, Protein Binding, Protein Structure, Quaternary, Static Electricity, Type C Phospholipases genetics, rac1 GTP-Binding Protein genetics, Isoenzymes chemistry, Isoenzymes metabolism, Type C Phospholipases chemistry, Type C Phospholipases metabolism, rac1 GTP-Binding Protein chemistry, rac1 GTP-Binding Protein metabolism
Abstract

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.

Published
2006
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