Crystal structure of MICU2 and comparison with MICU1 reveal insights into the uniporter gating mechanism.

Publication Type:

Journal Article


Proc Natl Acad Sci U S A, Volume 116, Issue 9, p.3546-3555 (2019)


Animals, Binding Sites, Calcium, Calcium Channels, Calcium-Binding Proteins, Crystallography, X-Ray, Dimerization, EF Hand Motifs, HeLa Cells, Humans, Mice, Mitochondria, Mitochondrial Membrane Transport Proteins, Protein Conformation, Protein Structure, Secondary


<p>The mitochondrial uniporter is a Ca-channel complex resident within the organelle&#39;s inner membrane. In mammalian cells the uniporter&#39;s activity is regulated by Ca due to concerted action of MICU1 and MICU2, two paralogous, but functionally distinct, EF-hand Ca-binding proteins. Here we present the X-ray structure of the apo form of MICU2 at 2.5-Å resolution. The core structure of MICU2 is very similar to that of MICU1. It consists of two lobes, each containing one canonical Ca-binding EF-hand (EF1, EF4) and one structural EF-hand (EF2, EF3). Two molecules of MICU2 form a symmetrical dimer stabilized by highly conserved hydrophobic contacts between exposed residues of EF1 of one monomer and EF3 of another. Similar interactions stabilize MICU1 dimers, allowing exchange between homo- and heterodimers. The tight EF1-EF3 interface likely accounts for the structural and functional coupling between the Ca-binding sites in MICU1, MICU2, and their complex that leads to the previously reported Ca-binding cooperativity and dominant negative effect of mutation of the Ca-binding sites in either protein. The N- and C-terminal segments of the two proteins are distinctly different. In MICU2 the C-terminal helix is significantly longer than in MICU1, and it adopts a more rigid structure. MICU2&#39;s C-terminal helix is dispensable in vitro for its interaction with MICU1 but required for MICU2&#39;s function in cells. We propose that in the MICU1-MICU2 oligomeric complex the C-terminal helices of both proteins form a central semiautonomous assembly which contributes to the gating mechanism of the uniporter.</p>