Crystal structure of Rac1 bound to its effector phospholipase C-β2

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-β2 (PLC-β2), a classic effector of heterotrimeric G proteins...

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Veröffentlicht in:Nature structural & molecular biology 2006-12, Vol.13 (12), p.1135-1140
Hauptverfasser: Sondek, John, Jezyk, Mark R, Snyder, Jason T, Gershberg, Svetlana, Worthylake, David K, Harden, T Kendall
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Sprache:eng
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Zusammenfassung: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-β2 (PLC-β2), a classic effector of heterotrimeric G proteins. Rac1 engages the pleckstrin-homology (PH) domain of PLC-β2 to optimize its orientation for substrate membranes. Gβγ also engages the PH domain to activate PLC-β2, and these two activation events are compatible, leading to additive stimulation of phospholipase activity. In contrast to PLC-δ, the PH domain of PLC-β2 cannot bind phosphoinositides, eliminating this mode of regulation. The structure of the Rac1–PLC-β2 complex reveals determinants that dictate selectivity of PLC-β isozymes for Rac GTPases over other Rho-family GTPases, and substitutions within PLC-β2 abrogate its stimulation by Rac1 but not by Gβγ, allowing for functional dissection of this integral signaling node.
ISSN:1545-9993
1545-9985
DOI:10.1038/nsmb1175