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| - | [[Image:3bic.jpg|left|200px]]<br /><applet load="3bic" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="3bic, resolution 2.60Å" /> | |
| - | '''Crystal structure of human methylmalonyl-CoA mutase'''<br /> | |
| | | | |
| - | ==About this Structure== | + | ==Crystal structure of human methylmalonyl-CoA mutase== |
| - | 3BIC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CL:'>CL</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Methylmalonyl-CoA_mutase Methylmalonyl-CoA mutase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.4.99.2 5.4.99.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BIC OCA].
| + | <StructureSection load='3bic' size='340' side='right'caption='[[3bic]], [[Resolution|resolution]] 2.60Å' scene=''> |
| - | [[Category: Homo sapiens]] | + | == Structural highlights == |
| - | [[Category: Methylmalonyl-CoA mutase]] | + | <table><tr><td colspan='2'>[[3bic]] is a 2 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=3BIC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BIC FirstGlance]. <br> |
| - | [[Category: Single protein]] | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> |
| - | [[Category: Arrowsmith, C H.]]
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr> |
| - | [[Category: Delft, F von.]] | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3bic FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bic OCA], [https://pdbe.org/3bic PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bic RCSB], [https://www.ebi.ac.uk/pdbsum/3bic PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bic ProSAT]</span></td></tr> |
| - | [[Category: Edwards, A M.]] | + | </table> |
| - | [[Category: Gileadi, O.]]
| + | == Disease == |
| - | [[Category: Kochan, G.]] | + | [https://www.uniprot.org/uniprot/MUTA_HUMAN MUTA_HUMAN] Defects in MUT are the cause of methylmalonic aciduria type mut (MMAM) [MIM:[https://omim.org/entry/251000 251000]. MMAM is an often fatal disorder of organic acid metabolism. Common clinical features include lethargy, vomiting, failure to thrive, hypotonia, neurological deficit and early death. Two forms of the disease are distinguished by the presence (mut-) or absence (mut0) of residual enzyme activity. Mut0 patients have more severe neurological manifestations of the disease than do MUT- patients. MMAM is unresponsive to vitamin B12 therapy.<ref>PMID:1977311</ref> <ref>PMID:1670635</ref> <ref>PMID:1351030</ref> <ref>PMID:1346616</ref> <ref>PMID:7912889</ref> <ref>PMID:7909321</ref> <ref>PMID:9285782</ref> <ref>PMID:9452100</ref> <ref>PMID:9554742</ref> <ref>PMID:10923046</ref> <ref>PMID:11350191</ref> <ref>PMID:15643616</ref> <ref>PMID:15781192</ref> <ref>PMID:16281286</ref> |
| - | [[Category: Oppermann, U.]] | + | == Function == |
| - | [[Category: Pantic, N.]]
| + | [https://www.uniprot.org/uniprot/MUTA_HUMAN MUTA_HUMAN] Involved in the degradation of several amino acids, odd-chain fatty acids and cholesterol via propionyl-CoA to the tricarboxylic acid cycle. MCM has different functions in other species. |
| - | [[Category: Parizotto, E.]] | + | == Evolutionary Conservation == |
| - | [[Category: Pike, A C.W.]] | + | [[Image:Consurf_key_small.gif|200px|right]] |
| - | [[Category: Pilka, E S.]] | + | Check<jmol> |
| - | [[Category: SGC, Structural Genomics Consortium.]]
| + | <jmolCheckbox> |
| - | [[Category: Ugochukwu, E.]] | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bi/3bic_consurf.spt"</scriptWhenChecked> |
| - | [[Category: Weigelt, J.]]
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| - | [[Category: CL]]
| + | <text>to colour the structure by Evolutionary Conservation</text> |
| - | [[Category: cobalamin]] | + | </jmolCheckbox> |
| - | [[Category: cobalt]]
| + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3bic ConSurf]. |
| - | [[Category: disease mutation]]
| + | <div style="clear:both"></div> |
| - | [[Category: isomerase]]
| + | <div style="background-color:#fffaf0;"> |
| - | [[Category: metabolic disease]]
| + | == Publication Abstract from PubMed == |
| - | [[Category: metal-binding]]
| + | 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. |
| - | [[Category: methylmalonyl coa mutase deficiency]]
| + | |
| - | [[Category: mitochondrion]] | + | |
| - | [[Category: organic aciduria]] | + | |
| - | [[Category: polymorphism]] | + | |
| - | [[Category: sgc]]
| + | |
| - | [[Category: structural genomics]]
| + | |
| - | [[Category: structural genomics consortium]]
| + | |
| - | [[Category: transit peptide]]
| + | |
| | | | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 19:05:53 2008''
| + | 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<ref>PMID:20876572</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 3bic" style="background-color:#fffaf0;"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Arrowsmith CH]] |
| | + | [[Category: Edwards AM]] |
| | + | [[Category: Gileadi O]] |
| | + | [[Category: Kochan G]] |
| | + | [[Category: Oppermann U]] |
| | + | [[Category: Pantic N]] |
| | + | [[Category: Parizotto E]] |
| | + | [[Category: Pike ACW]] |
| | + | [[Category: Pilka ES]] |
| | + | [[Category: Ugochukwu E]] |
| | + | [[Category: Weigelt J]] |
| | + | [[Category: Von Delft F]] |
| Structural highlights
Disease
MUTA_HUMAN Defects in MUT are the cause of methylmalonic aciduria type mut (MMAM) [MIM:251000. MMAM is an often fatal disorder of organic acid metabolism. Common clinical features include lethargy, vomiting, failure to thrive, hypotonia, neurological deficit and early death. Two forms of the disease are distinguished by the presence (mut-) or absence (mut0) of residual enzyme activity. Mut0 patients have more severe neurological manifestations of the disease than do MUT- patients. MMAM is unresponsive to vitamin B12 therapy.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
Function
MUTA_HUMAN Involved in the degradation of several amino acids, odd-chain fatty acids and cholesterol via propionyl-CoA to the tricarboxylic acid cycle. MCM has different functions in other species.
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[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jansen R, Ledley FD. Heterozygous mutations at the mut locus in fibroblasts with mut0 methylmalonic acidemia identified by polymerase-chain-reaction cDNA cloning. Am J Hum Genet. 1990 Nov;47(5):808-14. PMID:1977311
- ↑ Raff ML, Crane AM, Jansen R, Ledley FD, Rosenblatt DS. Genetic characterization of a MUT locus mutation discriminating heterogeneity in mut0 and mut- methylmalonic aciduria by interallelic complementation. J Clin Invest. 1991 Jan;87(1):203-7. PMID:1670635 doi:http://dx.doi.org/10.1172/JCI114972
- ↑ Crane AM, Martin LS, Valle D, Ledley FD. Phenotype of disease in three patients with identical mutations in methylmalonyl CoA mutase. Hum Genet. 1992 May;89(3):259-64. PMID:1351030
- ↑ Crane AM, Jansen R, Andrews ER, Ledley FD. Cloning and expression of a mutant methylmalonyl coenzyme A mutase with altered cobalamin affinity that causes mut- methylmalonic aciduria. J Clin Invest. 1992 Feb;89(2):385-91. PMID:1346616 doi:http://dx.doi.org/10.1172/JCI115597
- ↑ Crane AM, Ledley FD. Clustering of mutations in methylmalonyl CoA mutase associated with mut- methylmalonic acidemia. Am J Hum Genet. 1994 Jul;55(1):42-50. PMID:7912889
- ↑ Qureshi AA, Crane AM, Matiaszuk NV, Rezvani I, Ledley FD, Rosenblatt DS. Cloning and expression of mutations demonstrating intragenic complementation in mut0 methylmalonic aciduria. J Clin Invest. 1994 Apr;93(4):1812-9. PMID:7909321 doi:http://dx.doi.org/10.1172/JCI117166
- ↑ Janata J, Kogekar N, Fenton WA. Expression and kinetic characterization of methylmalonyl-CoA mutase from patients with the mut- phenotype: evidence for naturally occurring interallelic complementation. Hum Mol Genet. 1997 Sep;6(9):1457-64. PMID:9285782
- ↑ Adjalla CE, Hosack AR, Matiaszuk NV, Rosenblatt DS. A common mutation among blacks with mut- methylmalonic aciduria. Hum Mutat. 1998;Suppl 1:S248-50. PMID:9452100
- ↑ Adjalla CE, Hosack AR, Gilfix BM, Lamothe E, Sun S, Chan A, Evans S, Matiaszuk NV, Rosenblatt DS. Seven novel mutations in mut methylmalonic aciduria. Hum Mutat. 1998;11(4):270-4. PMID:9554742 doi:<270::AID-HUMU3>3.0.CO;2-T 10.1002/(SICI)1098-1004(1998)11:4<270::AID-HUMU3>3.0.CO;2-T
- ↑ Fuchshuber A, Mucha B, Baumgartner ER, Vollmer M, Hildebrandt F. mut0 methylmalonic acidemia: eleven novel mutations of the methylmalonyl CoA mutase including a deletion-insertion mutation. Hum Mutat. 2000 Aug;16(2):179. PMID:10923046 doi:<179::AID-HUMU17>3.0.CO;2-R 10.1002/1098-1004(200008)16:2<179::AID-HUMU17>3.0.CO;2-R
- ↑ Berger I, Shaag A, Anikster Y, Baumgartner ER, Bar-Meir M, Joseph A, Elpeleg ON. Mutation analysis of the MCM gene in Israeli patients with mut(0) disease. Mol Genet Metab. 2001 May;73(1):107-10. PMID:11350191 doi:10.1006/mgme.2001.3166
- ↑ Acquaviva C, Benoist JF, Pereira S, Callebaut I, Koskas T, Porquet D, Elion J. Molecular basis of methylmalonyl-CoA mutase apoenzyme defect in 40 European patients affected by mut(o) and mut- forms of methylmalonic acidemia: identification of 29 novel mutations in the MUT gene. Hum Mutat. 2005 Feb;25(2):167-76. PMID:15643616 doi:10.1002/humu.20128
- ↑ Martinez MA, Rincon A, Desviat LR, Merinero B, Ugarte M, Perez B. Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants. Mol Genet Metab. 2005 Apr;84(4):317-25. Epub 2005 Jan 22. PMID:15781192 doi:S1096-7192(04)00307-5
- ↑ Worgan LC, Niles K, Tirone JC, Hofmann A, Verner A, Sammak A, Kucic T, Lepage P, Rosenblatt DS. Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Hum Mutat. 2006 Jan;27(1):31-43. PMID:16281286 doi:10.1002/humu.20258
- ↑ 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
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