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EBioMedicine. 2020 Jan 6;51:102607. doi: 10.1016/j.ebiom.2019.102607. [Epub ahead of print]

Structural insights and activating mutations in diverse pathologies define mechanisms of deregulation for phospholipase C gamma enzymes.

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Discovery Sciences, R&D, AstraZeneca, Cambridge, CB4 0WG, UK.
Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK.
Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, UK.
European Molecular Biology Laboratory, Structural and Computational Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Drug Discovery Group, Translational Research Office, School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
Cambridge Cryo-EM Pharmaceutical Consortium, Thermo Fisher Scientific, 11 JJ Thomson Avenue, Madingley Road, Cambridge, CB3 0FF, UK.
Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, UK; Department for Cell Physiology and Metabolism, University of Geneva, Centre Medical Universitaire, Rue Michel-Servet 1, CH-1211 Geneva 4, Switzerland.
Discovery Sciences, R&D, AstraZeneca, Cambridge, CB4 0WG, UK. Electronic address:



PLCγ enzymes are key nodes in cellular signal transduction and their mutated and rare variants have been recently implicated in development of a range of diseases with unmet need including cancer, complex immune disorders, inflammation and neurodegenerative diseases. However, molecular nature of activation and the impact and dysregulation mechanisms by mutations, remain unclear; both are critically dependent on comprehensive characterization of the intact PLCγ enzymes.


For structural studies we applied cryo-EM, cross-linking mass spectrometry and hydrogen-deuterium exchange mass spectrometry. In parallel, we compiled mutations linked to main pathologies, established their distribution and assessed their impact in cells and in vitro.


We define structure of a complex containing an intact, autoinhibited PLCγ1 and the intracellular part of FGFR1 and show that the interaction is centred on the nSH2 domain of PLCγ1. We define the architecture of PLCγ1 where an autoinhibitory interface involves the cSH2, spPH, TIM-barrel and C2 domains; this relative orientation occludes PLCγ1 access to its substrate. Based on this framework and functional characterization, the mechanism leading to an increase in PLCγ1 activity for the largest group of mutations is consistent with the major, direct impact on the autoinhibitory interface.


We reveal features of PLCγ enzymes that are important for determining their activation status. Targeting such features, as an alternative to targeting the PLC active site that has so far not been achieved for any PLC, could provide new routes for clinical interventions related to various pathologies driven by PLCγ deregulation. FUND: CR UK, MRC and AstaZeneca.


Disease-linked variants; Mechanism; Phospholipase C gamma; Structure

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