9i3r
Human TRPM4 ion channel in MAASTY copolymer lipid nanodisc in a calcium-bound state
Structural highlights
DiseaseTRPM4_HUMAN Familial progressive cardiac conduction defect;Brugada syndrome. The disease is caused by mutations affecting the gene represented in this entry. FunctionTRPM4_HUMAN Calcium-activated non selective (CAN) cation channel that mediates membrane depolarization. While it is activated by increase in intracellular Ca(2+), it is impermeable to it. Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane. It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. Participates in T-cell activation by modulating Ca(2+) oscillations after T lymphocyte activation, which is required for NFAT-dependent IL2 production. Involved in myogenic constriction of cerebral arteries. Controls insulin secretion in pancreatic beta-cells. May also be involved in pacemaking or could cause irregular electrical activity under conditions of Ca(2+) overload. Affects T-helper 1 (Th1) and T-helper 2 (Th2) cell motility and cytokine production through differential regulation of calcium signaling and NFATC1 localization. Enhances cell proliferation through up-regulation of the beta-catenin signaling pathway.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedAmphiphilic copolymers capable of extracting membrane proteins directly from cellular membranes into "native nanodiscs" offer a simplified approach for preparing membrane proteins in lipid nanodiscs compared to approaches that rely on detergent. Copolymer amphiphilicity, length, and composition influence their performance, in addition to the protein itself and the purification conditions used. Here, we report a copolymer composed of methacrylic acid and styrene, which we term MAASTY, leveraging the inherent monomer reactivity ratios to create an anionic copolymer with a statistical distribution of monomers. We show that MAASTY can be used for high-resolution structural determination of a human membrane protein by single particle cryo-electron microscopy, preserving endogenous lipids including cholesterol and exhibiting an enrichment of phosphatidylinositol. Moreover, MAASTY copolymers effectively solubilize a broad range of lipid species and a wide range of different, eukaryotic membrane proteins from mammalian cells. We find that MAASTY copolymers are promising as effective solubilizers of membrane proteins and offer a chemical platform for structural and functional characterization of membrane proteins in native nanodiscs. MAASTY: a (dis)ordered copolymer for structural determination of human membrane proteins in native nanodiscs.,Pugh CF, Feilen LP, Zivkovic D, Praestegaard KF, Sideris C, Borthwick NJ, de Lichtenberg C, Bolla JR, Autzen AAA, Autzen HE Nat Commun. 2025 Dec 10;16(1):11399. doi: 10.1038/s41467-025-66208-7. PMID:41372170[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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