Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B 12 delivery and repair.
Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B 12 delivery and repair.
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用于 B 12 递送和修复的人类 G 蛋白-甲基丙二酸单酰辅酶 A 变位酶纳米组件的结构。
DOI：
10.1101/2023.03.23.533963
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Banerjee,Ruma
中科院分区：
文献类型：
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作者：
Mascarenhas,Romila;Ruetz,Markus;Gouda,Harsha;Heitman,Natalie;Yaw,Madeline;Banerjee,Ruma
G-蛋白在金属运输中起着分子开关的作用，为辅因子易位提供动力，并提供保真度。G蛋白MMAA与腺苷转移酶MMAB一起，协调B12依赖的人甲基丙二酰辅酶A突变酶(MMUT)的辅因子传递和修复。该复合体组装和移动 >；1300 Da货物的机制，或者在疾病中失败的机制，人们知之甚少。在这里，我们报道了人的MMUT-MMAA纳米组装的晶体结构，发现B12结构域戏剧性地旋转了180°，将其暴露在溶剂中。该复合体由MMAA楔入两个MMUT结构域之间，导致开关I和III环的有序化，揭示了变位酶依赖的GTPase激活的分子基础。该结构解释了甲基丙二酸尿症引起的突变所引起的生化惩罚，这些突变位于我们在这里确定的MMAA-MMUT界面。
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 B12domain, 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.