PLC-gamma
November 2021
Phospholipase C (PLC) enzymes play an important role in the regulation of intracellular signaling cascades. Once activated by the tyrosine kinases (e.g., EGFR, FGFR), they convert membrane lipid phosphatidylinositol - 4,5 – biphosphate (PIP2) into two intracellular second messengers - inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). The IP3 further triggers calcium release, and DAG mediates the activation of the protein kinase C, which causes different cellular responses.
The PLC gamma is one of the 13 PLC mammalian isoforms and it exists as two variants (PLCγ1 and PLCγ2) that can be found in different tissues. This enzyme has been linked to various diseases, and thus has been extensively studied in the last years. Its mutations and dysregulation are found in cancers, inflammation, autoimmune and neurodegenerative disorders. Scientists are working on gathering novel structural insights to further understand PLCγ controlling mechanisms and develop therapeutic strategies.
The PLCγ consists of a core region (N-terminal PH domain, two pairs of EF-hands, TIM-barrel and a C2 domain) that is commonly shared by most PLCs. However, gamma enzymes are unique for their additional regulatory domains (spPH, n- and c-SH2 and SH3 domains).The structural insights of each domain were so far obtained separately using X-Ray crystallography.
However, what was missing was information on how these domains relate to each other and how PLCγ interacts with the regulatory kinases.
The first intact, full-length human PLCγ structure has been solved in complex with the FGFR kinase domain using an integrative structural biology approach (Cryo EM, cross-linking mass spectrometry, and hydrogen-deuterium exchange mass spectrometry). The structure shows how the core region interacts with several regulatory domains in the so-called autoinhibition interface. Mutations that occur in this contact point of two regions can therefore hinder the enzyme autoinhibition. Further insights gained from the newly solved structure are related to the binding of FGFR kinase to the PLCγ SH2 domain.
Kinase-induced phosphorylation triggers conformational changes in the regulatory domains which result in the loss of domain contacts formed in the autoinhibition interface and allow for substrate binding. The resolved structure, therefore, sheds light on the PLCγ activation mechanism as well as how mutational changes can cause dysregulation.
3decision - Projects with human PLC gamma structures from the PDB
But to get the full picture of enzymes’ activity, one structure alone is not enough. The previously released PLCγ structures offer valuable insights that should not be neglected. Therefore, the best way to relate new data to prior knowledge is to centralize and to have easy access to it. In 3decision, you can gather structural knowledge by keeping the target structures and related metadata organized in Projects. Here you can store public and in-house experimental structures, homology models, ligands libraries, and associated files. Such a coherent system allows you to overcome the hardship of navigating through data and use the increasing knowledge to facilitate structural analytics and rational drug discovery.