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
• Assuntos: Aciduria ; Crystal structure ; Methylmalonyl-CoA mutase ; Molecular machines ; Mutation ; Protein transport ; Proteins ; Switches ; Translocation
• É parte de: Nature communications, 2023-07, Vol.14 (1), p.4332-4332, Article 4332
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• Descrição: 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 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° 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.
  
• Editor: London: Nature Publishing Group
  
• Idioma: Inglês