Characterization of the membrane interactions of phospholipase Cγ reveals key features of the active enzyme
Open accessAbstract
PLCγ enzymes are autoinhibited in resting cells and form key components of intracellular signaling that are also linked to disease development. Insights into physiological and aberrant activation of PLCγ require understanding of an active, membrane-bound form, which can hydrolyze inositol-lipid substrates. Here, we demonstrate that PLCγ1 cannot bind membranes unless the autoinhibition is disrupted. Through extensive molecular dynamics simulations and experimental evidence, we characterize membrane binding by the catalytic core domains and reveal previously unknown sites of lipid interaction. The identified sites act in synergy, overlap with autoinhibitory interfaces, and are shown to be critical for the phospholipase activity in cells. This work provides direct evidence that PLCγ1 is inhibited through obstruction of its membrane-binding surfaces by the regulatory region and that activation must shift PLCγ1 to a conformation competent for membrane binding. Knowledge of the critical sites of membrane interaction extends the mechanistic framework for activation, dysregulation, and therapeutic intervention.
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PLCγ1 shares 52% sequence identity with PLCγ2, and their overall domain organisation is conserved; therefore, homology models are plausible.
“PLCγ1 shares 52% sequence identity with PLCγ2, and their overall domain organisation is conserved; therefore, homology models are plausible.”
From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as Le Huray et al., 2022
The Discussion (page not provided) says PLCγ1 and PLCγ2 share a distinctive regulatory array, supporting conserved domain organisation. Our copy does not give 52% sequence identity between them or explicitly assess the plausibility of homology models; the 98% identity reported in Materials and Methods concerns rat and human PLCγ1. (LLM, conf=0.86)
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Non-inositol 1,4,5-trisphosphate (IP3) receptor IP3-binding proteins
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Heterozygous variants in PLCG1 affect hearing, vision, cardiac, and immune functionPreprint
Ma, M., Zheng, Y., Deng, M., Lu, S., Pan, X., Luo, X., Etoundi, M., Li‐Kroeger, D., Worley, K. C., Burrage, L. C., et al. (2025) · eLife · doi:10.7554/elife.95887.2
Bunney, T. D., Nyvall, H. G., Macrae, C., Lalović, D., Gregory, A., Huray, K. I. P. L., Harvey, N., Pinotsis, N., Kalli, A. C., Waudby, C. A., et al. (2025) · Biochemical Journal · doi:10.1042/bcj20253358
Self-citationRoque‐Borda, C. A., Sharma, A., Pavan, F. R., de la Torre, B. G., & Alberício, F. (2026) · Aggregate · doi:10.1002/agt2.70332
When a PLC-γ1–based light switch tells a cell which way to go
Sun, J., & Chen, M. (2026) · The Journal of Cell Biology · doi:10.1083/jcb.202605005
Methods for the establishment of enzymatic mechanisms – from QM to ML
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LAT condensation gates PLCγ1 activation via bimodal LAT phosphorylation
Ren, H., Lee, H., Omar, Y. A. D., DeGrandchamp, J. B., Hung, C., Eisen, T. J., Stamou, D. G., Kuriyan, J., Chakraborty, A. K., & Groves, J. T. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2614738123
- Authors
- Le Huray, K. I. P., Bunney, T. D., Pinotsis, N., Kalli, A. C., & Katan, M.
- Affiliations
- Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
- Institute of Structural and Molecular Biology (GB)
- University of Leeds (GB)
- Corresponding author
- Bunney, Tom D.
- Kalli, Antreas C.
- Katan, Matilda
- Venue
- Science Advances
- Published
- 2022-06-24
- Volume
- 8
- Issue
- 25
- Pages
- eabp9688-eabp9688
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC9232102
- OpenAlex
- W4283400061
- Cited by
- 21
- References
- 74
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 4 · 2023: 3 · 2022: 2
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Science Advances (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (221543/Z/20/Z)
- British Heart Foundation (PG/21/10515)
- Medical Research Council (MR/P028160/1, MC_PC_MR/T032774/1)
- Biotechnology and Biological Sciences Research Council (BB/M011151/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- phospholipase C-gamma1, membrane binding, autoinhibition, enzyme activation, catalytic core domain, inositol lipid hydrolysis, intracellular signaling, molecular dynamics simulation, protein-lipid interactions
- MeSH terms
- Lipids, Signal Transduction, Catalytic Domain
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