02519nas a2200253   4500008004100000022001400041245012800055210006900183260000800252300000900260490000700269520167800276100002901954700001701983700000502000700001602005700001802021700001902039700002002058700002002078700001902098700001702117856013102134       2026                        eng d  a1059-152400aNoncanonical regulation of the plasma membrane copper transporter CTRL through modulation of membrane mechanical properties0 aNoncanonical regulation of the plasma membrane copper transporte  cFEB  aar130 v373 a<p>
	We describe a noncanonical, membrane receptor-like regulation of the human copper transporter-1 (CTR1) in response to copper stimuli. CTR1 is the sole high-affinity trimeric plasma-membrane copper-importing channel that self-regulates by undergoing endocytosis to limit copper uptake. We observed that preceding copper-induced endocytosis, CTR1 forms clusters on the plasma membrane, a phenomenon that is typically observed in membrane receptors. We deciphered the mechanism of CTR1 clustering and studied its ramifications on the physical properties of plasma membranes harboring these clusters that could favor endocytosis. Membrane tension and fluctuation are fundamental regulators of pre-and post-endocytic events. Using coarse-grain molecular dynamics (MD)-simulations and coupled interference reflection microscopy-total internal reflection fluorescence microscopy (TIRF) we demonstrated that CTR1 clusters induce positive membrane curvature, an increase in local membrane tension, and a decrease in local membrane fluctuation; alterations that favor the formation of endocytic pits. Clustering is facilitated by copper sequestering methionine-rich extracellular amino-terminus of CTR1. MD-simulations and IRM-TIRF imaging revealed that CTR1 clustering is facilitated by membrane cholesterol, depletion of which delays CTR1 endocytosis. CTR1 clustering promotes clathrin-coated pit formation that engages recruitment of adaptor protein AP-2. To summarize, we report hitherto unknown ``pre-endocytic'' ``receptor-like'' phenomenon of ligand-induced clustering of a metal channel, which in turn regulates self-endocytosis by modulating membrane properties.</p>
1 aChatterjee, Subhendu, K.1 aKar, Sumanta1 a1 aDash, Tisha1 aGhosh, Tanmoy1 aPaul, Mrittika1 aMaji, Saptarshi1 aSengupta, Durba1 aSinha, Bidisha1 aGupta, Arnab  uhttps://library.ncl.res.in/content/noncanonical-regulation-plasma-membrane-copper-transporter-ctrl-through-modulation-membrane