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2www

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Crystal Structure of Methylmalonic Acidemia Type A Protein

Structural highlights

2www is a 4 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 2.64Å
Ligands:	,
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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Vitamin B12 (cobalamin, Cbl) is essential to the function of two human enzymes, methionine synthase (MS) and methylmalonyl-CoA mutase (MUT). The conversion of dietary Cbl to its cofactor forms, methyl-Cbl (MeCbl) for MS and adenosyl-Cbl (AdoCbl) for MUT, located in the cytosol and mitochondria, respectively, requires a complex pathway of intracellular processing and trafficking. One of the processing proteins, MMAA (methylmalonic aciduria type A), is implicated in the mitochondrial assembly of AdoCbl into MUT and is defective in children from the cblA complementation group of cobalamin disorders. To characterize the functional interplay between MMAA and MUT, we have crystallized human MMAA in the GDP-bound form and human MUT in the apo, holo and substrate-bound ternary forms. Structures of both proteins reveal highly conserved domain architecture and catalytic machinery for ligand binding, yet they show substantially different dimeric assembly and interaction, compared to their bacterial counterparts. We show that MMAA exhibits GTPase activity that is modulated by MUT and that the two proteins interact in vitro and in vivo. Formation of a stable MMAA-MUT complex is nucleotide-selective for MMAA (GMPPNP over GDP) and apoenzyme-dependent for MUT. The physiological importance of this interaction is highlighted by a recently-identified homoallelic patient mutation of MMAA, G188R, which, we show, retains basal GTPase activity but has abrogated interaction. Together, our data point to a "gate-keeping" role for MMAA by favouring complex formation with MUT apoenzyme for AdoCbl assembly and releasing the AdoCbl-loaded holoenzyme from the complex, in a GTP-dependent manner.

Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-coa mutase and insight into their complex formation.,Froese DS, Kochan G, Muniz J, Wu X, Gileadi C, Ugochukwu E, Krysztofinska E, Gravel RA, Oppermann U, Yue WW J Biol Chem. 2010 Sep 28. PMID:20876572^[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
↑ 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

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2www"

@@ Line 3: / Line 3: @@
 <StructureSection load='2www' size='340' side='right'caption='[[2www]], [[Resolution|resolution]] 2.64&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2www]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WWW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WWW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2www]] is a 4 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=2WWW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WWW FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.64&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</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=2www FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2www OCA], [https://pdbe.org/2www PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2www RCSB], [https://www.ebi.ac.uk/pdbsum/2www PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2www 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>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 30: / Line 35: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Arrowsmith, C H]]
+[[Category: Arrowsmith CH]]
-[[Category: Bountra, C]]
+[[Category: Bountra C]]
-[[Category: Bray, J]]
+[[Category: Bray J]]
-[[Category: Burgess-Brown, N]]
+[[Category: Burgess-Brown N]]
-[[Category: Chaikuad, A]]
+[[Category: Chaikuad A]]
-[[Category: Delft, F von]]
+[[Category: Edwards A]]
-[[Category: Edwards, A]]
+[[Category: Froese DS]]
-[[Category: Froese, D S]]
+[[Category: Gileadi C]]
-[[Category: Gileadi, C]]
+[[Category: Gravel RA]]
-[[Category: Gravel, R A]]
+[[Category: Guo K]]
-[[Category: Guo, K]]
+[[Category: Kavanagh KL]]
-[[Category: Kavanagh, K L]]
+[[Category: Kochan G]]
-[[Category: Kochan, G]]
+[[Category: Krysztofinska E]]
-[[Category: Krysztofinska, E]]
+[[Category: Muniz JRC]]
-[[Category: Muniz, J R.C]]
+[[Category: Oppermann U]]
-[[Category: Oppermann, U]]
+[[Category: Phillips C]]
-[[Category: Phillips, C]]
+[[Category: Picaud S]]
-[[Category: Picaud, S]]
+[[Category: Pike ACW]]
-[[Category: Pike, A C.W]]
+[[Category: Pilka E]]
-[[Category: Pilka, E]]
+[[Category: Sethi R]]
-[[Category: Sethi, R]]
+[[Category: Weigelt J]]
-[[Category: Weigelt, J]]
+[[Category: Yue WW]]
-[[Category: Yue, W W]]
+[[Category: Von Delft F]]
-[[Category: Nucleotide-binding]]
-[[Category: Transport protein]]

2www

From Proteopedia

Current revision

Crystal Structure of Methylmalonic Acidemia Type A Protein

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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