RT Journal Article
SR Electronic
T1 Evolutionary divergence reveals the molecular basis of EMRE dependence of the human MCU
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000718
DO 10.26508/lsa.202000718
VO 3
IS 10
A1 Melissa JS MacEwen
A1 Andrew L Markhard
A1 Mert Bozbeyoglu
A1 Forrest Bradford
A1 Olga Goldberger
A1 Vamsi K Mootha
A1 Yasemin Sancak
YR 2020
UL https://www.life-science-alliance.org/content/3/10/e202000718.abstract
AB The mitochondrial calcium uniporter (MCU) is a calcium-activated calcium channel critical for signaling and bioenergetics. MCU, the pore-forming subunit of the uniporter, contains two transmembrane domains and is found in all major eukaryotic taxa. In amoeba and fungi, MCU homologs are sufficient to form a functional calcium channel, whereas human MCU exhibits a strict requirement for the metazoan protein essential MCU regulator (EMRE) for conductance. Here, we exploit this evolutionary divergence to decipher the molecular basis of human MCU’s dependence on EMRE. By systematically generating chimeric proteins that consist of EMRE-independent Dictyostelium discoideum MCU and Homo sapiens MCU (HsMCU), we converged on a stretch of 10 amino acids in D. discoideum MCU that can be transplanted to HsMCU to render it EMRE independent. We call this region in human MCU the EMRE dependence domain (EDD). Crosslinking experiments show that EMRE directly interacts with HsMCU at its transmembrane domains as well as the EDD. Our results suggest that EMRE stabilizes the EDD of MCU, permitting both channel opening and calcium conductance, consistent with recently published structures of MCU-EMRE.