8gju: Difference between revisions

Latest revision as of 05:28, 9 August 2023

Crystal structure of human methylmalonyl-CoA mutase (MMUT) in complex with methylmalonic acidemia type A protein (MMAA), coenzyme A, and GDP

Structural highlights

8gju is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.79Å
Ligands:	COA, GDP, MG
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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

[3] 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

[4] 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

[5] 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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[4]

[5]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8gju is ON HOLD  until Paper Publication
+==Crystal structure of human methylmalonyl-CoA mutase (MMUT) in complex with methylmalonic acidemia type A protein (MMAA), coenzyme A, and GDP==
+<StructureSection load='8gju' size='340' side='right'caption='[[8gju]], [[Resolution|resolution]] 2.79&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8gju]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8GJU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GJU FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.79&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=COA:COENZYME+A'>COA</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8gju FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gju OCA], [https://pdbe.org/8gju PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gju RCSB], [https://www.ebi.ac.uk/pdbsum/8gju PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gju ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/MMAA_HUMAN MMAA_HUMAN] Vitamin B12-responsive methylmalonic acidemia type cblA. The disease is caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/MMAA_HUMAN 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).<ref>PMID:20876572</ref> <ref>PMID:21138732</ref> <ref>PMID:28497574</ref> <ref>PMID:28943303</ref>
+<div style="background-color:#fffaf0;">
+== 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 &gt;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.
-Authors: Mascarenhas, R.M., Ruetz, M., Gouda, H., Yaw, M., Banerjee, R.
+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<ref>PMID:37468522</ref>
-Description: Crystal structure of human methylmalonyl-CoA mutase (MMUT) in complex with methylmalonic acidemia type A protein (MMAA), coenzyme A, and GDP
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Gouda, H]]
+<div class="pdbe-citations 8gju" style="background-color:#fffaf0;"></div>
-[[Category: Banerjee, R]]
+== References ==
-[[Category: Yaw, M]]
+<references/>
-[[Category: Ruetz, M]]
+__TOC__
-[[Category: Mascarenhas, R.M]]
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Banerjee R]]
+[[Category: Gouda H]]
+[[Category: Mascarenhas RM]]
+[[Category: Ruetz M]]
+[[Category: Yaw M]]

8gju: Difference between revisions

Latest revision as of 05:28, 9 August 2023

Crystal structure of human methylmalonyl-CoA mutase (MMUT) in complex with methylmalonic acidemia type A protein (MMAA), coenzyme A, and GDP

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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