Characterization of MCU-Binding Proteins MCUR1 and CCDC90B — Representatives of a Protein Family Conserved in Prokaryotes and Eukaryotic Organelles

Membrane-bound coiled-coil proteins are important mediators of signaling, fusion, and scaffolding. Here, we delineate a heterogeneous group of trimeric membrane-anchored proteins in prokaryotes and eukaryotic organelles with a characteristic head-neck-stalk-anchor architecture, in which a membrane-anchored coiled-coil stalk projects an N-terminal head domain via a β-layer neck. Based on sequence analysis, we identify different types of head domains and determine crystal structures of two representatives, the archaeal protein Kcr-0859 and the human CCDC90B, which possesses the most widespread head type. Using mitochondrial calcium uniporter regulator 1 (MCUR1), the functionally characterized paralog of CCDC90B, we study the role of individual domains, and find that the head interacts directly with the mitochondrial calcium uniporter (MCU) and is destabilized upon Ca2+ binding. Our data provide structural details of a class of membrane-bound coiled-coil proteins and identify the conserved head domain of the most widespread type as a mediator of their function. [Display omitted] •A family of membrane-anchored coiled-coil proteins has been identified•The crystal structures of human CCDC90B and archaeal Kcr-0859 have been solved•Structural models of human MCUR1 and prokaryotic homologs have been built•Characterization of MCUR1 has identified the head domain as a mediator of function Performing a bioinformatic analysis, Adlakha et al. identify a family of membrane-bound coiled-coil proteins and solve the structure of the human representative CCDC90A. They build structural models for MCUR1, a regulator of mitochondrial Ca2+ uptake, and bacterial homologs. Finally, they functionally analyze single domains and identify the head as the functional module.