6wdn

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==Cryo-EM structure of mitochondrial calcium uniporter holocomplex in low Ca2+==
==Cryo-EM structure of mitochondrial calcium uniporter holocomplex in low Ca2+==
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<StructureSection load='6wdn' size='340' side='right'caption='[[6wdn]]' scene=''>
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<StructureSection load='6wdn' size='340' side='right'caption='[[6wdn]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WDN OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6WDN FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6wdn]] is a 10 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WDN OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6WDN FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6wdn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wdn OCA], [http://pdbe.org/6wdn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6wdn RCSB], [http://www.ebi.ac.uk/pdbsum/6wdn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6wdn ProSAT]</span></td></tr>
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</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MICU2, EFHA1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), MICU1, CALC, CBARA1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), SMDT1, C22orf32, EMRE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), MCU, C10orf42, CCDC109A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6wdn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wdn OCA], [http://pdbe.org/6wdn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6wdn RCSB], [http://www.ebi.ac.uk/pdbsum/6wdn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6wdn ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[[http://www.uniprot.org/uniprot/MCU_HUMAN MCU_HUMAN]] Mitochondrial inner membrane calcium uniporter that mediates calcium uptake into mitochondria. Mitochondrial calcium homeostasis plays key roles in cellular physiology and regulates cell bioenergetics, cytoplasmic calcium signals and activation of cell death pathways. Activity is regulated by MICU1 and MICU2 that stimulate and inhibit MCU activity, respectively. Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake. Involved in buffering the amplitude of systolic calcium rises in cardiomyocytes.<ref>PMID:21685886</ref> <ref>PMID:21685888</ref> <ref>PMID:22822213</ref> <ref>PMID:22829870</ref> <ref>PMID:22904319</ref> <ref>PMID:23101630</ref> <ref>PMID:23178883</ref> <ref>PMID:24332854</ref> <ref>PMID:24560927</ref> [[http://www.uniprot.org/uniprot/MICU2_HUMAN MICU2_HUMAN]] Key regulator of mitochondrial calcium uniporter (MCU) required to limit calcium uptake by MCU when cytoplasmic calcium is low (PubMed:24503055, PubMed:24560927, PubMed:26903221). MICU1 and MICU2 form a disulfide-linked heterodimer that stimulate and inhibit MCU activity, depending on the concentration of calcium (PubMed:24560927). MICU2 acts as a gatekeeper of MCU that senses calcium level via its EF-hand domains: prevents channel opening at resting calcium, avoiding energy dissipation and cell-death triggering (PubMed:24560927).<ref>PMID:24503055</ref> <ref>PMID:24560927</ref> <ref>PMID:26387864</ref> <ref>PMID:26903221</ref> [[http://www.uniprot.org/uniprot/EMRE_HUMAN EMRE_HUMAN]] Essential regulatory subunit of the mitochondrial calcium uniporter complex (uniplex), a complex that mediates calcium uptake into mitochondria (PubMed:24231807, PubMed:26774479, PubMed:27099988). Required to bridge the calcium-sensing proteins MICU1 and MICU2 with the calcium-conducting subunit MCU (PubMed:24231807). Plays a central role in regulating the uniplex complex response to intracellular calcium signaling (PubMed:27099988). Acts by mediating activation of MCU and retention of MICU1 to the MCU pore, in order to ensure tight regulation of the uniplex complex and appropriate responses to intracellular calcium signaling (PubMed:27099988).<ref>PMID:24231807</ref> <ref>PMID:26774479</ref> <ref>PMID:27099988</ref> [[http://www.uniprot.org/uniprot/MICU1_HUMAN MICU1_HUMAN]] Key regulator of mitochondrial calcium uniporter (MCU) required to limit calcium uptake by MCU when cytoplasmic calcium is low. Acts as a gatekeeper that senses calcium level via its EF-hand domains and sets a threshold for mitochondrial calcium uptake by MCU, thereby preventing mitochondrial calcium overload. Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake. Induces T-helper 1-mediated autoreactivity, which is accompanied by the release of IFNG.<ref>PMID:16002733</ref> <ref>PMID:20693986</ref> <ref>PMID:23101630</ref> <ref>PMID:22904319</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Mitochondria take up Ca(2+) through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca(2+) signalling and cell death(1,2). In mammals, the uniporter complex (uniplex) contains four core components: the pore-forming MCU protein, the gatekeepers MICU1 and MICU2, and an auxiliary subunit, EMRE, essential for Ca(2+) transport(3-8). To prevent detrimental Ca(2+) overload, the activity of MCU must be tightly regulated by MICUs, which sense changes in cytosolic Ca(2+) concentrations to switch MCU on and off(9,10). Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and Ca(2+)-activated states. These structures define the architecture of this multicomponent Ca(2+)-uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. Our work provides a framework for understanding regulated Ca(2+) uptake in mitochondria, and could suggest ways of modulating uniporter activity to treat diseases related to mitochondrial Ca(2+) overload.
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Structure and mechanism of the mitochondrial Ca(2+) uniporter holocomplex.,Fan M, Zhang J, Tsai CW, Orlando BJ, Rodriguez M, Xu Y, Liao M, Tsai MF, Feng L Nature. 2020 Jun;582(7810):129-133. doi: 10.1038/s41586-020-2309-6. Epub 2020 May, 20. PMID:32494073<ref>PMID:32494073</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6wdn" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Fan M]]
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[[Category: Fan, M]]
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[[Category: Feng L]]
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[[Category: Feng, L]]
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[[Category: Zhang J]]
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[[Category: Zhang, J]]
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[[Category: Membrane protein]]

Revision as of 10:49, 17 June 2020

Cryo-EM structure of mitochondrial calcium uniporter holocomplex in low Ca2+

PDB ID 6wdn

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