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Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations
| Content Provider | Scilit |
|---|---|
| Author | Lee, Samuel K. Shanmughapriya, Santhanam Mok, Mac C. Y. Dong, Zhiwei Tomar, Dhanendra Carvalho, Edmund Rajan, Sudarsan Junop, Murray S. Madesh, Muniswamy Stathopulos, Peter B. |
| Copyright Year | 2016 |
| Description | Journal: Cell Chemical Biology Summary Calcium $(Ca^{2+}$) flux into the matrix is tightly controlled by the mitochondrial $Ca^{2+}$ uniporter (MCU) due to vital roles in cell death and bioenergetics. However, the precise atomic mechanisms of MCU regulation remain unclear. Here, we solved the crystal structure of the N-terminal matrix domain of human MCU, revealing a β-grasp-like fold with a cluster of negatively charged residues that interacts with divalent cations. Binding of $Ca^{2+}$ or $Mg^{2+}$ destabilizes and shifts the self-association equilibrium of the domain toward monomer. Mutational disruption of the acidic face weakens oligomerization of the isolated matrix domain and full-length human protein similar to cation binding and markedly decreases MCU activity. Moreover, mitochondrial $Mg^{2+}$ loading or blockade of mitochondrial $Ca^{2+}$ extrusion suppresses MCU $Ca^{2+}$-uptake rates. Collectively, our data reveal that the β-grasp-like matrix region harbors an MCU-regulating acidic patch that inhibits human MCU activity in response to $Mg^{2+}$ and $Ca^{2+}$ binding. |
| Related Links | http://europepmc.org/articles/pmc5035232?pdf=render https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035232/pdf http://www.cell.com/article/S2451945616302422/pdf |
| Ending Page | 1169 |
| Page Count | 13 |
| Starting Page | 1157 |
| e-ISSN | 24519448 |
| DOI | 10.1016/j.chembiol.2016.07.012 |
| Journal | Cell Chemical Biology |
| Issue Number | 9 |
| Volume Number | 23 |
| Language | English |
| Publisher | Elsevier BV |
| Publisher Date | 2016-08-25 |
| Access Restriction | Open |
| Subject Keyword | Journal: Cell Chemical Biology Mitochondrial Calcium Uniporter Magnesium Binding Mcu-regulating Acidic Patch |
| Content Type | Text |
| Resource Type | Article |
