6PBC

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

Summary for 6PBC

• Entry DOI: 10.2210/pdb6pbc/pdb
• Descriptor: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma,1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1, CALCIUM ION, SODIUM ION, ... (4 entities in total)
• Functional Keywords: 1-phosphatidylinositol 4, 5-bisphosphate phosphodiesterase gamma-1, hydrolase
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 1
• Total formula weight: 136019.99

Authors

Hajicek, N.,Sondek, J. (deposition date: 2019-06-13, release date: 2020-01-08, Last modification date: 2024-03-13)

Primary citation

Hajicek, N.,Keith, N.C.,Siraliev-Perez, E.,Temple, B.R.S.,Huang, W.,Zhang, Q.,Harden, T.K.,Sondek, J.
Structural basis for the activation of PLC-gamma isozymes by phosphorylation and cancer-associated mutations.
Elife, 8:-, 2019

PubMed Abstract: Direct activation of the human phospholipase C-γ isozymes (PLC-γ1, -γ2) 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-γ1 and PLC-γ2 is implicated in inflammation, autoimmunity, and cancer. Although structures of isolated domains from PLC-γ 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-γ 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-γ isozymes found in several cancers have a wide spectrum of activities, and highlights how these activities are tuned during disease.

PubMed: 31889510
DOI: 10.7554/eLife.51700

Experimental method

X-RAY DIFFRACTION (2.46 Å)