Department of Molecular Physiology and Biological Physics, Center for Molecular and Cell Physiology, University of Virginia, Charlottesville, VA, USA.
Department of Physics and Astronomy, Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA.
Nat Rev Mol Cell Biol. 2023 Feb;24(2):107-122. doi: 10.1038/s41580-022-00524-4. Epub 2022 Sep 2.
Transmembrane proteins comprise ~30% of the mammalian proteome, mediating metabolism, signalling, transport and many other functions required for cellular life. The microenvironment of integral membrane proteins (IMPs) is intrinsically different from that of cytoplasmic proteins, with IMPs solvated by a compositionally and biophysically complex lipid matrix. These solvating lipids affect protein structure and function in a variety of ways, from stereospecific, high-affinity protein-lipid interactions to modulation by bulk membrane properties. Specific examples of functional modulation of IMPs by their solvating membranes have been reported for various transporters, channels and signal receptors; however, generalizable mechanistic principles governing IMP regulation by lipid environments are neither widely appreciated nor completely understood. Here, we review recent insights into the inter-relationships between complex lipidomes of mammalian membranes, the membrane physicochemical properties resulting from such lipid collectives, and the regulation of IMPs by either or both. The recent proliferation of high-resolution methods to study such lipid-protein interactions has led to generalizable insights, which we synthesize into a general framework termed the 'functional paralipidome' to understand the mutual regulation between membrane proteins and their surrounding lipid microenvironments.
跨膜蛋白约占哺乳动物蛋白质组的 30%，它们介导代谢、信号转导、运输和许多其他细胞生命所需的功能。整合膜蛋白 (IMP) 的微环境与细胞质蛋白的微环境本质上不同，IMP 被组成和生物物理复杂的脂质基质溶剂化。这些溶剂化的脂质以各种方式影响蛋白质的结构和功能，从立体特异性、高亲和力的蛋白-脂相互作用到通过膜整体性质的调节。已经报道了各种转运蛋白、通道和信号受体的 IMP 溶剂化膜的功能调节的具体例子；然而，脂质环境调节 IMP 的普遍机制原则既没有得到广泛的认识，也没有完全理解。在这里，我们回顾了最近关于哺乳动物膜复杂脂类组、由这些脂质集体产生的膜物理化学性质以及 IMP 受到其中一种或两种调节之间相互关系的新见解。最近出现了许多研究这种脂质-蛋白相互作用的高分辨率方法，这些方法提供了普遍的见解，我们将这些见解综合到一个称为“功能拟脂组”的一般框架中，以了解膜蛋白与其周围脂质微环境之间的相互调节。
