Dimerization of MICU Proteins Controls Ca2+ Influx through the Mitochondrial Ca2+ Uniporter
The mitochondrial Ca2+ uniporter complex (MCUC) is responsible for Ca2+ influx into the mitochondrial matrix, playing critical roles in various mitochondrial functions. Eukaryotic MCUC consists of multiple subunits, and its Ca2+ influx activity is controlled by regulatory subunits, including mitocho...
Saved in:
Published in | Cell reports (Cambridge) Vol. 26; no. 5; pp. 1203 - 1212.e4 |
---|---|
Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier Inc
29.01.2019
Elsevier |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | The mitochondrial Ca2+ uniporter complex (MCUC) is responsible for Ca2+ influx into the mitochondrial matrix, playing critical roles in various mitochondrial functions. Eukaryotic MCUC consists of multiple subunits, and its Ca2+ influx activity is controlled by regulatory subunits, including mitochondrial Ca2+ uptake 1 (MICU1) and its paralogs (MICU2 and MICU3). However, the underlying mechanism remains unclear. Here, we determined multiple crystal structures of MICU2 and MICU3 from Homo sapiens. Our data demonstrate that distinct MICU protein N-domains determine the specific type of MICU dimers that perform the opposing roles in mitochondrial Ca2+ uptake at low cytosolic Ca2+ levels. In contrast, at high cytosolic Ca2+ levels, all MICU proteins undergo dimer rearrangement induced by Ca2+ binding, which releases the suppression of the MCUC pore-forming subunit and promotes the influx of large amounts of Ca2+. Altogether, our results elucidate the delicate mechanism of mitochondrial Ca2+ uptake regulation by MICU proteins.
[Display omitted]
•Structures of human MICU2 and MICU3 are determined•The N-domain topology of MICU2 (or MICU3) is distinct from that of MICU1•Distinct N-domains determine the different functions of MICU proteins•Mechanism of mitochondrial Ca2+ uptake regulation by MICU proteins is proposed
Xing et al. determine multiple crystal structures of human MICU2 and MICU3. They demonstrate that distinct MICU protein N-domains determine the specific type of MICU dimers that perform opposing roles in mitochondrial Ca2+ uptake at low cytosolic Ca2+ levels. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2019.01.022 |