Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair

Romila Mascarenhas, Markus Ruetz, Harsha Gouda, Natalie Heitman, Madeline Yaw and Ruma Banerjee ()
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Romila Mascarenhas: University of Michigan
Markus Ruetz: University of Michigan
Harsha Gouda: University of Michigan
Natalie Heitman: University of Michigan
Madeline Yaw: University of Michigan
Ruma Banerjee: University of Michigan

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. The G-protein, MMAA, together with MMAB, an adenosyltransferase, orchestrate cofactor delivery and repair of B12-dependent human methylmalonyl-CoA mutase (MMUT). The mechanism by which the complex assembles and moves a >1300 Da cargo, or fails in disease, are poorly understood. Herein, we report the crystal structure of the human MMUT-MMAA nano-assembly, which reveals a dramatic 180° rotation of the B12 domain, exposing it to solvent. The complex, stabilized by MMAA wedging between two MMUT domains, leads to ordering of the switch I and III loops, revealing the molecular basis of mutase-dependent GTPase activation. The structure explains the biochemical penalties incurred by methylmalonic aciduria-causing mutations that reside at the MMAA-MMUT interfaces we identify here.

Date: 2023
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DOI: 10.1038/s41467-023-40077-4

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