9b93
From Proteopedia
Cryo-EM structure of the human TRPM4 channel in the presence of EDTA at 37 degrees Celsius
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 PubMedTemperature profoundly affects macromolecular function, particularly in proteins with temperature sensitivity(1,2). However, its impact is often overlooked in biophysical studies that are typically performed at non-physiological temperatures, potentially leading to inaccurate mechanistic and pharmacological insights. Here we demonstrate temperature-dependent changes in the structure and function of TRPM4, a temperature-sensitive Ca(2+)-activated ion channel(3-7). By studying TRPM4 prepared at physiological temperature using single-particle cryo-electron microscopy, we identified a 'warm' conformation that is distinct from those observed at lower temperatures. This conformation is driven by a temperature-dependent Ca(2+)-binding site in the intracellular domain, and is essential for TRPM4 function in physiological contexts. We demonstrated that ligands, exemplified by decavanadate (a positive modulator)(8) and ATP (an inhibitor)(9), bind to different locations of TRPM4 at physiological temperatures than at lower temperatures(10,11), and that these sites have bona fide functional relevance. We elucidated the TRPM4 gating mechanism by capturing structural snapshots of its different functional states at physiological temperatures, revealing the channel opening that is not observed at lower temperatures. Our study provides an example of temperature-dependent ligand recognition and modulation of an ion channel, underscoring the importance of studying macromolecules at physiological temperatures. It also provides a potential molecular framework for deciphering how thermosensitive TRPM channels perceive temperature changes. Physiological temperature drives TRPM4 ligand recognition and gating.,Hu J, Park SJ, Walter T, Orozco IJ, O'Dea G, Ye X, Du J, Lu W Nature. 2024 May 15. doi: 10.1038/s41586-024-07436-7. PMID:38750366[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Du J | Hu J | Lu W
