Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B-12 delivery and repair

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 B-12-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 & DEG; rotation of the B-12 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. B-12-dependent human methylmalonly-CoA mutase (MMUT) requires the chaperone MMAA. The authors report the crystal structure of MMUT-MMAA, which shows a MMAA-driven conformational change in MMUT involved n B-12 loading and repair and helps explain the effects of disease-causing MMAA-MMUT interface mutations.

Automated summary

G-proteins and their cofactors MMAA and MMAB orchestrate cofactor translocation and repair in B-12-dependent human MMUT, and their crystal structure reveals a dramatic conformational change and the basis of GTPase activation. Disease-causing mutations at the MMAA-MMUT interfaces are explained by the structure.