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

Abstract
Data availability
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Abstract

Direct activation of the human phospholipase C-g isozymes (PLC-g1, -g2) 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-g1 and PLC-g2 is implicated in inflammation, autoimmunity, and cancer. Although structures of isolated domains from PLC-g 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-g 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-g isozymes found in several cancers have a wide spectrum of activities, and highlights how these activities are tuned during disease.

Data availability

Coordinates and structure factors for PLC-gamma1 are deposited in the Protein Data Bank under accession number 6PBC.

The following data sets were generated

1. Hajicek N
2. Sondek J
(2019) Structural basis for the activation of PLC-gamma isozymes by phosphorylation and cancer-associated mutations
Protein Data Bank, 6PBC.

https://www.rcsb.org/structure/6PBC

Article and author information

Author details

Nicole Hajicek

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-7457-4830
Nicholas C Keith

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States

Competing interests
No competing interests declared.
Edhriz Siraliev-Perez

Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States

Competing interests
No competing interests declared.
Brenda R S Temple

R L Juliano Structural Bioinformatics Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-9233-0191
Weigang Huang

Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, United States

Competing interests
No competing interests declared.
Qisheng Zhang

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States

Competing interests
No competing interests declared.
T Kendall Harden

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States

Competing interests
No competing interests declared.
John Sondek

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States

For correspondence
sondek@med.unc.edu

Competing interests
John Sondek, partial ownership of KXTbio, Inc. which licenses the production of WH-15.

"This ORCID iD identifies the author of this article:" 0000-0002-1127-8310

Funding

National Institutes of Health (R01-GM057391)

John Sondek

National Institutes of Health (R01-GM098894)

Qisheng Zhang
John Sondek

National Science Foundation (DGE-1650116)

Edhriz Siraliev-Perez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.