@article{b02300f278414d2eb82d642fb671615c,
title = "Structural Mechanism of EMRE-Dependent Gating of the Human Mitochondrial Calcium Uniporter",
abstract = "Mitochondrial calcium uptake is crucial to the regulation of eukaryotic Ca2+ homeostasis and is mediated by the mitochondrial calcium uniporter (MCU). While MCU alone can transport Ca2+ in primitive eukaryotes, metazoans require an essential single membrane-spanning auxiliary component called EMRE to form functional channels; however, the molecular mechanism of EMRE regulation remains elusive. Here, we present the cryo-EM structure of the human MCU-EMRE complex, which defines the interactions between MCU and EMRE as well as pinpoints the juxtamembrane loop of MCU and extended linker of EMRE as the crucial elements in the EMRE-dependent gating mechanism among metazoan MCUs. The structure also features the dimerization of two MCU-EMRE complexes along an interface at the N-terminal domain (NTD) of human MCU that is a hotspot for post-translational modifications. Thus, the human MCU-EMRE complex, which constitutes the minimal channel components among metazoans, provides a framework for future mechanistic studies on MCU. Structural analysis of the complex responsible for calcium import into human mitochondria shows how transporter gating is regulated.",
keywords = "calcium channel, intracellular calcium signaling, mitochondrial calcium uniporter",
author = "Yan Wang and Nguyen, {Nam X.} and Ji She and Weizhong Zeng and Yi Yang and Bai, {Xiao chen} and Youxing Jiang",
note = "Funding Information: Cryo-EM data were collected at the University of Texas Southwestern Medical Center Cryo-EM Facility, which is funded by the CPRIT Core Facility Support Award RP170644; we thank D. Nicastro and D. Stoddard for technical support and facility access. We also thank Drs. C. Miller and M-F. Tsai (HHMI/Brandeis University) for generously providing us with MCU−/−, EMRE−/−, and MCU−/−/EMRE−/− HEK293 cells and technical assistance with the mitochondrial calcium uptake assay. This work was supported in part by the Howard Hughes Medical Institute (to Y.J.), the NIH (grant GM079179 to Y.J.), the Welch Foundation (grant I-1578 to Y.J.), the Cancer Prevention and Research Institute of Texas (to X.-c.B.), and the Virginia Murchison Linthicum Scholar in Medical Research fund (to X.-c.B.). Y.W. N.X.N. and Y.J. conceived the study. Y.W. N.X.N. Y.J. and X.-c.B. designed the experiments and analyzed the data. Y.W. N.X.N. W.Z. Y.Y. and X.-c.B. generated key materials and executed the experiments. N.X.N. Y.W. and Y.J. wrote the manuscript with input from X.-c.B. Y.J. supervised the project and revised the manuscript. The authors declare no competing interests. Funding Information: Cryo-EM data were collected at the University of Texas Southwestern Medical Center Cryo-EM Facility, which is funded by the CPRIT Core Facility Support Award RP170644 ; we thank D. Nicastro and D. Stoddard for technical support and facility access. We also thank Drs. C. Miller and M-F. Tsai (HHMI/Brandeis University) for generously providing us with MCU −/− , EMRE −/− , and MCU −/− /EMRE −/− HEK293 cells and technical assistance with the mitochondrial calcium uptake assay. This work was supported in part by the Howard Hughes Medical Institute (to Y.J.), the NIH (grant GM079179 to Y.J.), the Welch Foundation (grant I-1578 to Y.J.), the Cancer Prevention and Research Institute of Texas (to X.-c.B.), and the Virginia Murchison Linthicum Scholar in Medical Research fund (to X.-c.B.). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = may,
day = "16",
doi = "10.1016/j.cell.2019.03.050",
language = "English (US)",
volume = "177",
pages = "1252--1261.e13",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}