Structural basis for the activation of PLC-? isozymes by phosphorylation and cancer-associated mutations.

ABSTRACT: Direct activation of the human phospholipase C-? isozymes (PLC-?1, -?2) by tyrosine phosphorylation is fundamental to the control of diverse biological processes, including chemotaxis, platelet aggregation, and adaptive immunity. In turn, aberrant activation of PLC-?1 and PLC-?2 is implicated in inflammation, autoimmunity, and cancer. Although structures of isolated domains from PLC-? isozymes are available, these structures are insufficient to define how release of basal autoinhibition is coupled to phosphorylation-dependent enzyme activation. Here, we describe the first high-resolution structure of a full-length PLC-? isozyme and use it to underpin a detailed model of their membrane-dependent regulation. Notably, an interlinked set of regulatory domains integrates basal autoinhibition, tyrosine kinase engagement, and additional scaffolding functions with the phosphorylation-dependent, allosteric control of phospholipase activation. The model also explains why mutant forms of the PLC-? isozymes found in several cancers have a wide spectrum of activities, and highlights how these activities are tuned during disease.

SUBMITTER: Hajicek N 

PROVIDER: S-EPMC7004563 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature