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Molecular mechanisms of phospholipase C ?3 autoinhibition.

ABSTRACT: Phospholipase C ? (PLC?) enzymes are dramatically activated by heterotrimeric G proteins. Central to this response is the robust autoinhibition of PLC? by the X-Y linker region within its catalytic core and by the H?2' helix in the C-terminal extension of the enzyme. The molecular mechanism of each and their mutual dependence are poorly understood. Herein, it is shown that distinct regions within the X-Y linker have specific roles in regulating activity. Most important,an acidic stretch within the linker stabilizes a lid that occludes the active site, consistent with crystal structures of variants lacking this region. Inhibition by the H?2' helix is independent of the X-Y linker and likely regulates activity by limiting membrane interaction of the catalytic core. Full activation of PLC? thus requires multiple independent molecular events induced by membrane association of the catalytic core and by the binding of regulatory proteins.

SUBMITTER: Lyon AM

PROVIDER: S-EPMC4308481 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Molecular mechanisms of phospholipase C β3 autoinhibition.

Lyon Angeline M AM Begley Jessica A JA Manett Taylor D TD Tesmer John J G JJG

Structure (London, England : 1993) 20141201 12

Phospholipase C β (PLCβ) enzymes are dramatically activated by heterotrimeric G proteins. Central to this response is the robust autoinhibition of PLCβ by the X-Y linker region within its catalytic core and by the Hα2' helix in the C-terminal extension of the enzyme. The molecular mechanism of each and their mutual dependence are poorly understood. Herein, it is shown that distinct regions within the X-Y linker have specific roles in regulating activity. Most important,an acidic stretch within t ...[more]

PMID: 25435326

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