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

Hajicek, Nicole; Keith, Nicholas C; Siraliev-Perez, Edhriz; Temple, Brenda; Huang, Wentao; Zhang, Qisheng; Harden, T. Kendall; Sondek, John

doi:10.7554/elife.51700

Cited by 59 publications

(130 citation statements)

References 90 publications

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“…Therefore, the molecular mechanisms that lead to an increase in PLC activity in diverse pathologies could be similar. Considerable supporting evidence is consistent with a model where PLCγ2 is kept in an inactive state by extensive intramolecular interactions between the regulatory domains (including cSH2 and spPH domains) and the PLC-core domains [11,31]. Release of this autoinhibition by physiological stimulation (via phosphorylation) or by mutations represents an important step leading to an increase in PLC activity.…”

Section: Discussionsupporting

confidence: 76%

Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations

et al. 2020

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Autoinflammatory diseases (AIDs) were first described as clinical disorders characterized by recurrent episodes of seemingly unprovoked sterile inflammation. In the past few years, the identification of novel AIDs expanded their phenotypes toward more complex clinical pictures associating vasculopathy, autoimmunity, or immunodeficiency. Herein, we describe two unrelated patients suffering since the neonatal period from a complex disease mainly characterized by severe sterile inflammation, recurrent bacterial infections, and marked humoral immunodeficiency. Whole-exome sequencing detected a novel, de novo heterozygous PLCG2 variant in each patient (p.Ala708Pro and p.Leu845_Leu848del). A clear enhanced PLCγ2 activity for both variants was demonstrated by both ex vivo calcium responses of the patient’s B cells to IgM stimulation and in vitro assessment of PLC activity. These data supported the autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) diagnosis in both patients. Immunological evaluation revealed a severe decrease of immunoglobulins and B cells, especially class-switched memory B cells, with normal T and NK cell counts. Analysis of bone marrow of one patient revealed a reduced immature B cell fraction compared with controls. Additional investigations showed that both PLCG2 variants activate the NLRP3-inflammasome through the alternative pathway instead of the canonical pathway. Collectively, the evidences here shown expand APLAID diversity toward more severe phenotypes than previously reported including dominantly inherited agammaglobulinemia, add novel data about its genetic basis, and implicate the alternative NLRP3-inflammasome activation pathway in the basis of sterile inflammation.

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Section: Discussionsupporting

confidence: 76%

Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations

et al. 2020

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“…This PLC is sperm-specific and is the physiological trigger responsible for generating I(1,4,5)P 3 -mediated Ca 2+ oscillations that induces oocyte activation during mammalian fertilisation [43,44]. A substantial number of 3D structures for PLC enzymes provide a valuable basis for the understanding of various functional properties at the molecular level, including their PLC activity and regulatory mechanisms [45][46][47][48][49]. Notably, despite the diversity of their interacting proteins, the general molecular mechanism for regulation of PLCs is centred on intramolecular interactions that maintain PLCs in their inactive form, also referred to as autoinhibition, that becomes released in the process of activation.…”

Section: Plc Signalling Plc Families Their Regulation and Biologicalmentioning

confidence: 99%

Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane

Katan

Cockcroft

2020

Essays in Biochemistry

104

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Phosphatidylinositol(4,5) bisphosphate (PI(4,5)P2) has become a major focus in biochemistry, cell biology and physiology owing to its diverse functions at the plasma membrane. As a result, the functions of PI(4,5)P2 can be explored in two separate and distinct roles – as a substrate for phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K) and as a primary messenger, each having unique properties. Thus PI(4,5)P2 makes contributions in both signal transduction and cellular processes including actin cytoskeleton dynamics, membrane dynamics and ion channel regulation. Signalling through plasma membrane G-protein coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and immune receptors all use PI(4,5)P2 as a substrate to make second messengers. Activation of PI3K generates PI(3,4,5)P3 (phosphatidylinositol(3,4,5)trisphosphate), a lipid that recruits a plethora of proteins with pleckstrin homology (PH) domains to the plasma membrane to regulate multiple aspects of cellular function. In contrast, PLC activation results in the hydrolysis of PI(4,5)P2 to generate the second messengers, diacylglycerol (DAG), an activator of protein kinase C and inositol(1,4,5)trisphosphate (IP3/I(1,4,5)P3) which facilitates an increase in intracellular Ca2+. Decreases in PI(4,5)P2 by PLC also impact on functions that are dependent on the intact lipid and therefore endocytosis, actin dynamics and ion channel regulation are subject to control. Spatial organisation of PI(4,5)P2 in nanodomains at the membrane allows for these multiple processes to occur concurrently.

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“…The dimer interfaces are formed in part by conserved hydrophobic surfaces of EF hands 3/4 (EF3/4) and the TIM barrel domain that might be expected to interact with the PH domain and EF1/2 if they were present, based on structures of other PLC enzymes 12,23,25,26 .…”

Section: And 2; Supplementary Tables 1 and 2)mentioning

confidence: 99%

Structure of phospholipase Cε reveals an integrated RA1 domain and previously unidentified regulatory elements

et al. 2020

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Phospholipase Cε (PLCε) generates lipid-derived second messengers at the plasma and perinuclear membranes in the cardiovascular system. It is activated in response to a wide variety of signals, such as those conveyed by Rap1A and Ras, through a mechanism that involves its C-terminal Ras association (RA) domains (RA1 and RA2). However, the complexity and size of PLCε has hindered its structural and functional analysis. Herein, we report the 2.7 Å crystal structure of the minimal fragment of PLCε that retains basal activity. This structure includes the RA1 domain, which forms extensive interactions with other core domains. A conserved amphipathic helix in the autoregulatory X-Y linker of PLCε is also revealed, which we show modulates activity in vitro and in cells. The studies provide the structural framework for the core of this critical cardiovascular enzyme that will allow for a better understanding of its regulation and roles in disease.

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

Cited by 59 publications

References 90 publications

Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations

Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations

Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane

Structure of phospholipase Cε reveals an integrated RA1 domain and previously unidentified regulatory elements

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