Calcium is a main signalling effector in eukaryotic cells. Therefore, its cellular concentration is tightly regulated through processes of calcium increase and decrease. Among decrease processes, mitochondria are organelles capable of buffering high concentrations of calcium, and by doing so, they become central on cellular signalling and survival. In humans, mitochondrial calcium uptake is mediated by a protein called MCU.
Function
MCU is a highly selective uniporter that allows calcium entry into the mitochondrial matrix. In metazoa, it belongs to a protein complex entitled Mitochondrial Calcium Uniporter Complex (MCUC) along with EMRE, MICU1 and MICU2, which are respectively proposed as a regulator and gatekeepers of the complex.
Structure
Being assembled as a tetramer, MCU monomers posses 351 amino acid residues. Each subunit can be divided into four structural domains, them being N-terminal domain (NTD), linker helix domain (LHD), coiled-coil domain (CCD), and transmembrane domain (TMD). CCD and TMD are the pore-forming subunits, while LHD links this regions to NTD. Recently, regulation of the complex and dimerization of two tetrameres were reported as functions of NTD.
To guarantee selectivity, 260WDIMEP265, a highly conserved sequence among protein homologues, from each monomer form two filters. The first one, dependent of D261 residues has a radius of affinity for hydrated calcium. The narrower one, is stabilized by E264 and its selective for calcium radius. Finally, there’s a second constriction point at the end of the pore, formed by residues E288 and V290 of each monomer, that are involved in a juxtamembrane loop (JML).
Disease
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