Sandbox Reserved 1626: Difference between revisions
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===Movement of Calcium=== | ===Movement of Calcium=== | ||
Microscopy has revealed three sites in the MCU channel of roughly spherical density equally spaced 6Å apart.<ref name="Baradaran"/> Sites 1 and 2 lie within the selectivity filter so they can easily be assumed to contain calcium, but site 3 could be calcium or some other small molecule.<ref name="Baradaran"/> Site 1 is positioned in the ring formed by Asp225 residues and there is a distance of 4Å between the center of the site and each carboxylate group indicating presence of water.<ref name="Baradaran"/> The second site is positioned in the ring formed by Glu228 and there is a distance of 2.8Å between the carboxylate group of each residue and the middle of the site indicating absence of water.<ref name="Baradaran"/> It is hypothesized that one calcium ion coordinated with water in site 1 loses its water and moves to site 2 and a calcium ion moves from the IMS into site 1.<ref name="Baradaran"/> Meanwhile, a different calcium ion moves from site 2 to site 3 or the mitochondrial matrix.<ref name="Baradaran"/> | Microscopy has revealed three sites in the MCU channel of roughly spherical density equally spaced 6Å apart.<ref name="Baradaran"/> Sites 1 and 2 lie within the selectivity filter so they can easily be assumed to contain calcium, but site 3 could be calcium or some other small molecule.<ref name="Baradaran"/> Site 1 is positioned in the ring formed by Asp225 residues and there is a distance of 4Å between the center of the site and each [https://en.wikipedia.org/wiki/Carboxylate carboxylate group] indicating presence of water.<ref name="Baradaran"/> The second site is positioned in the ring formed by Glu228 and there is a distance of 2.8Å between the carboxylate group of each residue and the middle of the site indicating absence of water.<ref name="Baradaran"/> It is hypothesized that one calcium ion coordinated with water in site 1 loses its water and moves to site 2 and a calcium ion moves from the IMS into site 1.<ref name="Baradaran"/> Meanwhile, a different calcium ion moves from site 2 to site 3 or the mitochondrial matrix.<ref name="Baradaran"/> | ||
===Mutations=== | ===Mutations=== | ||
There are a number of mutations that completely eliminate calcium uptake by the MCU. For example, mutation of W,D,E, or P of the WDXXEP motif altered the highly conserved selectivity filter and completely eliminated calcium uptake.<ref name="Baradaran"/><ref name="Fan"/> For example, even mutating Glu228 to an aspartate significantly changed the dimensions of the pore and inhibited uptake of calcium.<ref name="Baradaran"/> However, mutation of either X residue was not detrimental to calcium uptake.<ref name="Baradaran"/> Furthermore, mutation of a tyrosine residue directly below the selectivity filter substantially impaired calcium intake and proper protein folding.<ref name="Fan"/> The residue on TM1 that affected calcium uptake the most in human MCU was Trp317 which has a side chain constituting a primary contact point between TM1 and TM2.<ref name="Fan"/> Mutation of Phe326 or Gly331 of the TM1-TM2 linker in human MCU affected the linker conformation and configuration of the pore entrance and impaired calcium intake.<ref name="Fan"/> | There are a number of mutations that completely eliminate calcium uptake by the MCU. For example, mutation of [https://en.wikipedia.org/wiki/Tryptophan W], [https://en.wikipedia.org/wiki/Aspartic_acid D], [https://en.wikipedia.org/wiki/Glutamic_acid E], or [https://en.wikipedia.org/wiki/Proline P] of the WDXXEP motif altered the highly conserved selectivity filter and completely eliminated calcium uptake.<ref name="Baradaran"/><ref name="Fan"/> For example, even mutating Glu228 to an aspartate significantly changed the dimensions of the pore and inhibited uptake of calcium.<ref name="Baradaran"/> However, mutation of either X residue was not detrimental to calcium uptake.<ref name="Baradaran"/> Furthermore, mutation of a tyrosine residue directly below the selectivity filter substantially impaired calcium intake and proper protein folding.<ref name="Fan"/> The residue on TM1 that affected calcium uptake the most in human MCU was Trp317 which has a side chain constituting a primary contact point between TM1 and TM2.<ref name="Fan"/> Mutation of Phe326 or Gly331 of the TM1-TM2 linker in human MCU affected the linker conformation and configuration of the pore entrance and impaired calcium intake.<ref name="Fan"/> | ||
==Regulation and Inhibition== | ==Regulation and Inhibition== | ||
