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

Autor: Mascarenhas, Romila, Ruetz, Markus, Gouda, Harsha, Heitman, Natalie, Yaw, Madeline, Banerjee, Ruma
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Zdroj: Nature Communications; 7/19/2023, Vol. 14 Issue 1, p1-11, 11p
Abstrakt: 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. B12-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 B12 loading and repair and helps explain the effects of disease-causing MMAA-MMUT interface mutations. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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