Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK.
Department of Neuroscience, Physiology and Pharmacology, Division of Biosciences, University College London, 21 University Street, London WC1E 6JJ, UK.
Prog Lipid Res. 2020 Nov;80:101065. doi: 10.1016/j.plipres.2020.101065. Epub 2020 Sep 20.
Phosphoinositide-specific phospholipase Cs (PLCs) are expressed in all mammalian cells and play critical roles in signal transduction. To obtain a comprehensive understanding of these enzymes in physiology and pathology, a detailed structural, biochemical, cell biological and genetic information is required. In this review, we cover all these aspects to summarize current knowledge of the entire superfamily. The families of PLCs have expanded from 13 enzymes to 16 with the identification of the atypical PLCs in the human genome. Recent structural insights highlight the common themes that cover not only the substrate catalysis but also the mechanisms of activation. This involves the release of autoinhibitory interactions that, in the absence of stimulation, maintain classical PLC enzymes in their inactive forms. Studies of individual PLCs provide a rich repertoire of PLC function in different physiologies. Furthermore, the genetic studies discovered numerous mutated and rare variants of PLC enzymes and their link to human disease development, greatly expanding our understanding of their roles in diverse pathologies. Notably, substantial evidence now supports involvement of different PLC isoforms in the development of specific cancer types, immune disorders and neurodegeneration. These advances will stimulate the generation of new drugs that target PLC enzymes, and will therefore open new possibilities for treatment of a number of diseases where current therapies remain ineffective.
磷酸肌醇特异性磷脂酶 C（PLCs）存在于所有哺乳动物细胞中，在信号转导中发挥着关键作用。为了全面了解这些在生理和病理条件下的酶，需要详细的结构、生化、细胞生物学和遗传学信息。在这篇综述中，我们涵盖了所有这些方面，总结了整个超家族的现有知识。随着人类基因组中鉴定出非典型 PLC，PLC 家族已从 13 种酶扩展到 16 种。最近的结构研究强调了共同的主题，不仅涵盖了底物催化，还涵盖了激活机制。这涉及到自动抑制相互作用的释放，在没有刺激的情况下，这种相互作用使经典 PLC 酶保持在非活性形式。对单个 PLC 的研究提供了 PLC 在不同生理学中的丰富功能。此外，遗传研究发现了大量 PLC 酶的突变和罕见变体及其与人类疾病发展的联系，极大地扩展了我们对它们在各种病理条件下作用的理解。值得注意的是，大量证据表明，不同的 PLC 同工型参与了特定癌症类型、免疫紊乱和神经退行性疾病的发展。这些进展将刺激针对 PLC 酶的新药的产生，从而为目前治疗效果不佳的许多疾病的治疗开辟新的可能性。
