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bioRxiv · 10.1101/2023.03.23.533963

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

Mascarenhas, R.·Ruetz, M.·Gouda, H.·Heitman, N.·Yaw, M.·Banerjee, R.
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Abstract

G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. MMAA, a G-protein motor, together with MMAB, an adenosyltransferase, orchestrate cofactor delivery and repair of B12-dependent human methylmalonyl-CoA mutase (MMUT). The mechanism by which the motor 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 nanomotor assembly, which reveals a dramatic 180{degrees} rotation of the B12 domain, exposing it to solvent. The nanomotor 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 newly identified MMAA-MMUT interfaces.

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Mascarenhas, R., Ruetz, M., Gouda, H., Heitman, N., Yaw, M., Banerjee, R.. 2023-03-23. Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. https://doi.org/10.1101/2023.03.23.533963

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