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The role of phospholipase C? on the plasma membrane and in the cytosol: How modular domains enable novel functions.

ABSTRACT: Phospholipase C? (PLC?) is a signaling enzyme activated by G proteins to generate calcium signals. The catalytic core of PLC? is surrounded by modular domains that mediate the interaction of the enzyme with known protein partners on the plasma membrane. The C-terminal region PLC? contains a novel coiled-coil domain that is required for G?q binding and activation. Recent work has shown that this domain also binds a number of cytosolic proteins that regulate protein translation, and that these proteins compete with G?q for PLC? binding. The ability of PLC? to shuttle between the cytosol to impact protein translation and the plasma membrane to mediate calcium signals puts PLC? in a central role in cell function.

SUBMITTER: Scarlata S

PROVIDER: S-EPMC6732780 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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The role of phospholipase Cβ on the plasma membrane and in the cytosol: How modular domains enable novel functions.

Scarlata Suzanne S

Advances in biological regulation 20190729

Phospholipase Cβ (PLCβ) is a signaling enzyme activated by G proteins to generate calcium signals. The catalytic core of PLCβ is surrounded by modular domains that mediate the interaction of the enzyme with known protein partners on the plasma membrane. The C-terminal region PLCβ contains a novel coiled-coil domain that is required for Gαq binding and activation. Recent work has shown that this domain also binds a number of cytosolic proteins that regulate protein translation, and that these pro ...[more]

PMID: 31409535

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Project description:Phospholipases C (PLCs) reversibly associate with membranes to hydrolyze phosphatidylinositol-4, 5-bisphosphate (PI[4,5]P(2)) and comprise four main classes: beta, gamma, delta, and epsilon. Most eukaryotic PLCs contain a single, N-terminal pleckstrin homology (PH) domain, which is thought to play an important role in membrane targeting. The structure of a single PLC PH domain, that from PLCdelta1, has been determined; this PH domain binds PI(4,5)P(2) with high affinity and stereospecificity and has served as a paradigm for PH domain functionality. However, experimental studies demonstrate that PH domains from different PLC classes exhibit diverse modes of membrane interaction, reflecting the dissimilarity in their amino acid sequences. To elucidate the structural basis for their differential membrane-binding specificities, we modeled the three-dimensional structures of all mammalian PLC PH domains by using bioinformatic tools and calculated their biophysical properties by using continuum electrostatic approaches. Our computational analysis accounts for a large body of experimental data, provides predictions for those PH domains with unknown functions, and indicates functional roles for regions other than the canonical lipid-binding site identified in the PLCdelta1-PH structure. In particular, our calculations predict that (1). members from each of the four PLC classes exhibit strikingly different electrostatic profiles than those ordinarily observed for PH domains in general, (2). nonspecific electrostatic interactions contribute to the membrane localization of PLCdelta-, PLCgamma-, and PLCbeta-PH domains, and (3). phosphorylation regulates the interaction of PLCbeta-PH with its effectors through electrostatic repulsion. Our molecular models for PH domains from all of the PLC classes clearly demonstrate how a common structural fold can serve as a scaffold for a wide range of surface features and biophysical properties that support distinctive functional roles.

Dataset Information

The role of phospholipase C? on the plasma membrane and in the cytosol: How modular domains enable novel functions.

Publications

The role of phospholipase Cβ on the plasma membrane and in the cytosol: How modular domains enable novel functions.

Similar Datasets

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