Structural insights and activating mutations in diverse pathologies define mechanisms of deregulation for phospholipase C gamma enzymes
| العنوان: | Structural insights and activating mutations in diverse pathologies define mechanisms of deregulation for phospholipase C gamma enzymes |
|---|---|
| المؤلفون: | Tom D. Bunney, Anne-Claude Gavin, Christopher D. Stubbs, Christopher R. Phillips, Kasim Sader, Taiana Maia de Oliveira, Sakshi Khosa, Mark Skehel, Katharina Beckenbauer, Matilda Katan, Trevor Askwith, Sarah L. Maslen, Kevin Macé, Yang Liu |
| المصدر: | EBioMedicine, Vol. 51 (2020) P. 102607 EBioMedicine, Vol 51, Iss, Pp-(2020) |
| بيانات النشر: | Elsevier BV, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, chemistry.chemical_classification, lcsh:R5-920, biology, Mechanism (biology), Fibroblast growth factor receptor 1, lcsh:R, lcsh:Medicine, Active site, General Medicine, Computational biology, Phospholipase C gamma, General Biochemistry, Genetics and Molecular Biology, In vitro, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Enzyme, Immune system, chemistry, 030220 oncology & carcinogenesis, biology.protein, lcsh:Medicine (General), ddc:612, Intracellular part |
| الوصف: | Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Keywords: Disease-linked variants, Phospholipase C gamma, Structure, Mechanism |
| تدمد: | 2352-3964 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::59ba6ff9655370fa90e635cb400763ef https://doi.org/10.1016/j.ebiom.2019.102607 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....59ba6ff9655370fa90e635cb400763ef |
| قاعدة البيانات: | OpenAIRE |
Full Text via ClinicalKey | تدمد: | 23523964 |
|---|