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

Nat Struct Mol Biol. 2006 Dec;13(12):1135-40. doi: 10.1038/nsmb1175. Epub 2006 Nov 19.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

  • Isoenzymes
  • Type C Phospholipases
  • PLCB2 protein, human
  • Phospholipase C beta
  • rac1 GTP-Binding Protein