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General and versatile autoinhibition of PLC isozymes.

ABSTRACT: 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-beta2 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-beta2 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.

SUBMITTER: Hicks SN

PROVIDER: S-EPMC2702322 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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General and versatile autoinhibition of PLC isozymes.

Hicks Stephanie N SN Jezyk Mark R MR Gershburg Svetlana S Seifert Jason P JP Harden T Kendall TK Sondek John J

Molecular cell 20080801 3

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-beta2 illustrates occlusion of the active site by a loop separating the two halves of the ...[more]

PMID: 18691970

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