| Structural highlights
Disease
MMAA_HUMAN Vitamin B12-responsive methylmalonic acidemia type cblA. The disease is caused by variants affecting the gene represented in this entry.
Function
MMAA_HUMAN GTPase, binds and hydrolyzes GTP (PubMed:28497574, PubMed:20876572, PubMed:21138732, PubMed:28943303). Involved in intracellular vitamin B12 metabolism, mediates the transport of cobalamin (Cbl) into mitochondria for the final steps of adenosylcobalamin (AdoCbl) synthesis (PubMed:28497574, PubMed:20876572). Functions as a G-protein chaperone that assists AdoCbl cofactor delivery from MMAB to the methylmalonyl-CoA mutase (MMUT) (PubMed:28497574, PubMed:20876572). Plays a dual role as both a protectase and a reactivase for MMUT (PubMed:21138732, PubMed:28943303). Protects MMUT from progressive inactivation by oxidation by decreasing the rate of the formation of the oxidized inactive cofactor hydroxocobalamin (OH2Cbl) (PubMed:21138732, PubMed:28943303). Additionally acts a reactivase by promoting the replacement of OH2Cbl by the active cofactor AdoCbl, restoring the activity of MMUT in the presence and hydrolysis of GTP (PubMed:21138732, PubMed:28943303).[1] [2] [3] [4]
Publication Abstract from PubMed
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 degrees 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.
Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair.,Mascarenhas R, Ruetz M, Gouda H, Heitman N, Yaw M, Banerjee R Nat Commun. 2023 Jul 19;14(1):4332. doi: 10.1038/s41467-023-40077-4. PMID:37468522[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Froese DS, Kochan G, Muniz J, Wu X, Gileadi C, Ugochukwu E, Krysztofinska E, Gravel RA, Oppermann U, Yue WW. Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-coa mutase and insight into their complex formation. J Biol Chem. 2010 Sep 28. PMID:20876572 doi:10.1074/jbc.M110.177717
- ↑ Takahashi-Íñiguez T, García-Arellano H, Trujillo-Roldán MA, Flores ME. Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein. Biochem Biophys Res Commun. 2011 Jan 7;404(1):443-7. PMID:21138732 doi:10.1016/j.bbrc.2010.11.141
- ↑ Plessl T, Bürer C, Lutz S, Yue WW, Baumgartner MR, Froese DS. Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria. Hum Mutat. 2017 Aug;38(8):988-1001. PMID:28497574 doi:10.1002/humu.23251
- ↑ Takahashi-Iñiguez T, González-Noriega A, Michalak C, Flores ME. Human MMAA induces the release of inactive cofactor and restores methylmalonyl-CoA mutase activity through their complex formation. Biochimie. 2017 Nov;142:191-196. PMID:28943303 doi:10.1016/j.biochi.2017.09.012
- ↑ Mascarenhas R, Ruetz M, Gouda H, Heitman N, Yaw M, Banerjee R. Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair. Nat Commun. 2023 Jul 19;14(1):4332. PMID:37468522 doi:10.1038/s41467-023-40077-4
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