Structural Mechanism of EMRE-Dependent Gating of the Human Mitochondrial Calcium Uniporter

Cell. 2019 May 16;177(5):1252-1261.e13. doi: 10.1016/j.cell.2019.03.050. Epub 2019 May 9.

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.

Keywords: calcium channel; intracellular calcium signaling; mitochondrial calcium uniporter.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • HEK293 Cells
  • Humans
  • Ion Channel Gating / physiology*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Protein Domains
  • Protein Multimerization / physiology*
  • Protein Structure, Secondary

Substances

  • Calcium Channels
  • Multiprotein Complexes
  • SMDT1 protein, human
  • mitochondrial calcium uniporter