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General and Versatile Autoinhibition of PLC Isozymes
Stephanie N. Hicks,1 Mark R. Jezyk,1,4 Svetlana Gershburg,1 Jason P. Seifert,1 T. Kendall Harden,1,2 and John Sondek1,2,3,
1 Department of Pharmacology, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
2 Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
3 Department of Biochemistry and Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Phospholipase C (PLC) isozymes are directly activated by heterotrimeric G proteins and Ras-like GTPases to hydrolyze phosphatidylinositol 4,5-bisphosphate into the second messengers diacylglycerol and inositol 1,4,5-trisphosphate. Although PLCs play central roles in myriad signaling cascades, the molecular details of their activation remain poorly understood. As described here, the crystal structure of PLC-β2 illustrates occlusion of the active site by a loop separating the two halves of the catalytic TIM barrel. Removal of this insertion constitutively activates PLC-β2 without ablating its capacity to be further stimulated by classical G protein modulators. Similar regulation occurs in other PLC members, and a general mechanism of interfacial activation at membranes is presented that provides a unifying framework for PLC activation by diverse stimuli.
