The structure of the MICU1‐MICU2 complex unveils the regulation of the mitochondrial calcium uniporter

• Published in: The EMBO journal 2020-10, Vol.39 (19), p.e104285-n/a
• Main Authors: Wu, Wenping, Shen, Qingya, Zhang, Ruiling, Qiu, Zhiyu, Wang, Youjun, Zheng, Jimin, Jia, Zongchao
• Format: Article
• Language: English
• Subjects: Accumulation; Activation; Binding; Calcium (mitochondrial); Calcium - chemistry; Calcium - metabolism; Calcium channels; Calcium Channels - chemistry; Calcium Channels - genetics; Calcium Channels - metabolism; Calcium homeostasis; Calcium influx; Calcium ions; Calcium signalling; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cation Transport Proteins - chemistry; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Channel gating; Competition; Crystal structure; Crystallography, X-Ray; EMBO20; EMBO40; EMRE; Grooves; Homeostasis; Humans; Hydrophobicity; Interfaces; Ion Transport; MICU1‐MICU2; Mitochondria; Mitochondrial Membrane Transport Proteins - chemistry; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; Multiprotein Complexes - chemistry; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Peptides; Regulation; Regulatory subunits; Structural analysis; Structure-function relationships; uniporter
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2019104285

The MICU1‐MICU2 heterodimer regulates the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake. Herein, we present two crystal structures of the MICU1‐MICU2 heterodimer, in which Ca 2+ ‐free and Ca 2+ ‐bound EF‐hands are observed in both proteins, revealing both electrostatic and hydrophobic interfaces. Furthermore, we show that MICU1 interacts with EMRE, another regulator of MCU, through a Ca 2+ ‐dependent alkaline groove. Ca 2+ binding strengthens the MICU1‐EMRE interaction, which in turn facilitates Ca 2+ uptake. Conversely, the MICU1‐MCU interaction is favored in the absence of Ca 2+ , thus inhibiting the channel activity. This Ca 2+ ‐dependent switch illuminates how calcium signals are transmitted from regulatory subunits to the calcium channel and the transition between gatekeeping and activation channel functions. Furthermore, competition with an EMRE peptide alters the uniporter threshold in resting conditions and elevates Ca 2+ accumulation in stimulated mitochondria, confirming the gatekeeper role of the MICU1‐MICU2 heterodimer. Taken together, these structural and functional data provide new insights into the regulation of mitochondrial calcium uptake. Synopsis The mitochondrial calcium uniporter (MCU) modulating calcium uptake and homeostasis in mitochondria is controlled by the regulatory subunits MICU1 and MICU2. Structural analysis of Ca 2+ ‐free and partial Ca 2+ ‐bound MICU1–MICU2 heterodimers reveals how calcium binding modulates gatekeeping and activation functions of the regulatory subunits. Electrostatic and hydrophobic interfaces are present in Ca 2+ ‐free and Ca 2+ ‐bound MICU1–MICU2 heterodimers, respectively. MICU1 interacts with the poly‐aspartate tail of another regulator, EMRE, via its Ca 2+ ‐dependent alkaline groove Ca 2+ allows EMRE to outcompete MCU for MICU1 binding, transforming MICU1–MICU2 from a gatekeeper to an activator of MCU. Competition with an EMRE peptide reduces the threshold of uniporter Ca 2+ uptake in resting conditions and increases Ca 2+ accumulation in mitochondria upon stimulation. Graphical Abstract Structural analysis of MICU1–MICU2 heterodimers reveals how Ca 2+ binding modulates gatekeeping and activation of the mitochondrial calcium uniporter.