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The crystal structure of MICU2 provides insight into Ca2+-binding and MICU1-MICU2 heterodimer formation

ABSTRACT: The Mitochondrial Calcium Uniporter (MCU) complex mediates the uptake of Ca2+ into mitochondria. Its activity is regulated by regulatory subunits such as EF-hands-containing MICU1 and MICU2. They form a heterodimer that acts as the main gatekeeper of the uniporter. Herein we report the crystal structure of human MICU2 at 1.96-Å resolution. Our structure reveals a dimeric architecture of MICU2, in which each monomer adopts the canonical two lobes structure with a pair of EF hands in each lobe. Both Ca2+-bound and Ca2+-free EF-hands are observed in our structure. Moreover, we have characterized the interaction sites within MICU2 homodimer, as well as the MICU1-MICU2 heterodimer in both Ca2+-free and Ca2+-bound conditions. Glu242 in MICU1 and Arg352 in MICU2 are crucial for apo heterodimer formation, while Phe383 in MICU1 and Glu196 in MICU2 significantly contribute to Ca2+-bound heterodimer. Taken together, structural and biochemical analyses have allowed us to establish plausible MICU1-MICU2 complex models which help understand the heterodimer conformational transition from apo to Ca2+-bound states, and explain its co-regulatory mechanism critical for MCU's mitochondrial calcium uptake function.

SUBMITTER: Dr. Wenping Wu

PROVIDER: S-SCDT-EMBOR-2018-47488V1 | biostudies-other |

REPOSITORIES: biostudies-other

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The crystal structure of MICU2 provides insight into Ca<sup>2+</sup> binding and MICU1-MICU2 heterodimer formation.

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