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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Romila Mascarenhas & Markus Ruetz & Harsha Gouda & Natalie Heitman & Madeline Yaw & Ruma Banerjee, 2023. "Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40077-4
    DOI: 10.1038/s41467-023-40077-4
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