5KUE

Human SeMet incorporated I141M/L146M mitochondrial calcium uniporter (residues 72-189) crystal structure with magnesium

Summary for 5KUE

• Entry DOI: 10.2210/pdb5kue/pdb
• Related: 5KUG 5KUI 5KUJ
• Descriptor: Calcium uniporter protein, mitochondrial, MAGNESIUM ION, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (5 entities in total)
• Functional Keywords: beta-grasp fold i141m/l146m se-met double mutant n-terminal domain residues 72-189 mitochondrial calcium uniporter, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 14305.49

Authors

Mok, C.Y.M.,Lee, S.K.,Junop, M.S.,Stathopulos, P.B. (deposition date: 2016-07-13, release date: 2016-09-07, Last modification date: 2024-11-13)

Primary citation

Lee, S.K.,Shanmughapriya, S.,Mok, M.C.,Dong, Z.,Tomar, D.,Carvalho, E.,Rajan, S.,Junop, M.S.,Madesh, M.,Stathopulos, P.B.
Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations.
Cell Chem Biol, 23:1157-1169, 2016

PubMed Abstract: 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.

PubMed: 27569754
DOI: 10.1016/j.chembiol.2016.07.012

Experimental method

X-RAY DIFFRACTION (1.5 Å)