|
|
| (2 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | + | |
| | ==Crystal Structure of an Aspartoacylase from Homo Sapiens== | | ==Crystal Structure of an Aspartoacylase from Homo Sapiens== |
| - | <StructureSection load='2i3c' size='340' side='right' caption='[[2i3c]], [[Resolution|resolution]] 2.80Å' scene=''> | + | <StructureSection load='2i3c' size='340' side='right'caption='[[2i3c]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2i3c]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2I3C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2I3C FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2i3c]] 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=2I3C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2I3C FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.8Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2gu2|2gu2]]</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=2i3c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i3c OCA], [https://pdbe.org/2i3c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2i3c RCSB], [https://www.ebi.ac.uk/pdbsum/2i3c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2i3c ProSAT], [https://www.topsan.org/Proteins/CESG/2i3c TOPSAN]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ASPA, ACY2, ASP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Aspartoacylase Aspartoacylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.15 3.5.1.15] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2i3c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i3c OCA], [http://pdbe.org/2i3c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2i3c RCSB], [http://www.ebi.ac.uk/pdbsum/2i3c PDBsum], [http://www.topsan.org/Proteins/CESG/2i3c TOPSAN]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/ACY2_HUMAN ACY2_HUMAN]] Defects in ASPA are the cause of Canavan disease (CAND) [MIM:[http://omim.org/entry/271900 271900]]; also known as spongy degeneration of the brain. CAND is a rare neurodegenerative condition of infancy or childhood characterized by white matter vacuolization and demeylination that gives rise to a spongy appearance. The clinical features are onset in early infancy, atonia of neck muscles, hypotonia, hyperextension of legs and flexion of arms, blindness, severe mental defect, megalocephaly, and death by 18 months on the average.<ref>PMID:8252036</ref> <ref>PMID:12706335</ref> <ref>PMID:8023850</ref> <ref>PMID:7668285</ref> <ref>PMID:7599639</ref> <ref>PMID:8659549</ref> <ref>PMID:9452117</ref> <ref>PMID:10564886</ref> <ref>PMID:10407784</ref> <ref>PMID:10909858</ref> <ref>PMID:12638939</ref> <ref>PMID:12205125</ref> | + | [https://www.uniprot.org/uniprot/ACY2_HUMAN ACY2_HUMAN] Defects in ASPA are the cause of Canavan disease (CAND) [MIM:[https://omim.org/entry/271900 271900]; also known as spongy degeneration of the brain. CAND is a rare neurodegenerative condition of infancy or childhood characterized by white matter vacuolization and demeylination that gives rise to a spongy appearance. The clinical features are onset in early infancy, atonia of neck muscles, hypotonia, hyperextension of legs and flexion of arms, blindness, severe mental defect, megalocephaly, and death by 18 months on the average.<ref>PMID:8252036</ref> <ref>PMID:12706335</ref> <ref>PMID:8023850</ref> <ref>PMID:7668285</ref> <ref>PMID:7599639</ref> <ref>PMID:8659549</ref> <ref>PMID:9452117</ref> <ref>PMID:10564886</ref> <ref>PMID:10407784</ref> <ref>PMID:10909858</ref> <ref>PMID:12638939</ref> <ref>PMID:12205125</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ACY2_HUMAN ACY2_HUMAN]] Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate. NAA occurs in high concentration in brain and its hydrolysis NAA plays a significant part in the maintenance of intact white matter. In other tissues it act as a scavenger of NAA from body fluids. | + | [https://www.uniprot.org/uniprot/ACY2_HUMAN ACY2_HUMAN] Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate. NAA occurs in high concentration in brain and its hydrolysis NAA plays a significant part in the maintenance of intact white matter. In other tissues it act as a scavenger of NAA from body fluids. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i3/2i3c_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i3/2i3c_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| Line 35: |
Line 33: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Aspartoacylase|Aspartoacylase]] | + | *[[Aminoacylase 3D structures|Aminoacylase 3D structures]] |
| | + | *[[Aspartoacylase 3D structures|Aspartoacylase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Aspartoacylase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Bingman, C A]] | + | [[Category: Bingman CA]] |
| - | [[Category: Bitto, E]] | + | [[Category: Bitto E]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Mccoy JG]] |
| - | [[Category: Mccoy, J G]] | + | [[Category: Phillips Jr GN]] |
| - | [[Category: Phillips, G N]] | + | [[Category: Wesenberg GE]] |
| - | [[Category: Wesenberg, G E]] | + | |
| - | [[Category: Acy2]]
| + | |
| - | [[Category: Aminoacylase-2]]
| + | |
| - | [[Category: Aspa]]
| + | |
| - | [[Category: Aspartoacylase family]]
| + | |
| - | [[Category: Canavan disease]]
| + | |
| - | [[Category: Cesg]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: N-acetyl-l-aspartate]]
| + | |
| - | [[Category: PSI, Protein structure initiative]]
| + | |
| - | [[Category: Zinc-dependent hydrolase]]
| + | |
| Structural highlights
Disease
ACY2_HUMAN Defects in ASPA are the cause of Canavan disease (CAND) [MIM:271900; also known as spongy degeneration of the brain. CAND is a rare neurodegenerative condition of infancy or childhood characterized by white matter vacuolization and demeylination that gives rise to a spongy appearance. The clinical features are onset in early infancy, atonia of neck muscles, hypotonia, hyperextension of legs and flexion of arms, blindness, severe mental defect, megalocephaly, and death by 18 months on the average.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Function
ACY2_HUMAN Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate. NAA occurs in high concentration in brain and its hydrolysis NAA plays a significant part in the maintenance of intact white matter. In other tissues it act as a scavenger of NAA from body fluids.
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
Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. Deficiency in this activity leads to spongiform degeneration of the white matter of the brain and is the established cause of Canavan disease, a fatal progressive leukodystrophy affecting young children. We present crystal structures of recombinant human and rat aspartoacylase refined to 2.8- and 1.8-A resolution, respectively. The structures revealed that the N-terminal domain of aspartoacylase adopts a protein fold similar to that of zinc-dependent hydrolases related to carboxypeptidases A. The catalytic site of aspartoacylase shows close structural similarity to those of carboxypeptidases despite only 10-13% sequence identity between these proteins. About 100 C-terminal residues of aspartoacylase form a globular domain with a two-stranded beta-sheet linker that wraps around the N-terminal domain. The long channel leading to the active site is formed by the interface of the N- and C-terminal domains. The C-terminal domain is positioned in a way that prevents productive binding of polypeptides in the active site. The structures revealed that residues 158-164 may undergo a conformational change that results in opening and partial closing of the channel entrance. We hypothesize that the catalytic mechanism of aspartoacylase is closely analogous to that of carboxypeptidases. We identify residues involved in zinc coordination, and propose which residues may be involved in substrate binding and catalysis. The structures also provide a structural framework necessary for understanding the deleterious effects of many missense mutations of human aspartoacylase.
Structure of aspartoacylase, the brain enzyme impaired in Canavan disease.,Bitto E, Bingman CA, Wesenberg GE, McCoy JG, Phillips GN Jr Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):456-61. Epub 2006 Dec 28. PMID:17194761[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kaul R, Gao GP, Balamurugan K, Matalon R. Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease. Nat Genet. 1993 Oct;5(2):118-23. PMID:8252036 doi:http://dx.doi.org/10.1038/ng1093-118
- ↑ Moore RA, Le Coq J, Faehnle CR, Viola RE. Purification and preliminary characterization of brain aspartoacylase. Arch Biochem Biophys. 2003 May 1;413(1):1-8. PMID:12706335
- ↑ Kaul R, Gao GP, Aloya M, Balamurugan K, Petrosky A, Michals K, Matalon R. Canavan disease: mutations among Jewish and non-Jewish patients. Am J Hum Genet. 1994 Jul;55(1):34-41. PMID:8023850
- ↑ Shaag A, Anikster Y, Christensen E, Glustein JZ, Fois A, Michelakakis H, Nigro F, Pronicka E, Ribes A, Zabot MT, et al.. The molecular basis of canavan (aspartoacylase deficiency) disease in European non-Jewish patients. Am J Hum Genet. 1995 Sep;57(3):572-80. PMID:7668285
- ↑ Kaul R, Gao GP, Michals K, Whelan DT, Levin S, Matalon R. Novel (cys152 > arg) missense mutation in an Arab patient with Canavan disease. Hum Mutat. 1995;5(3):269-71. PMID:7599639 doi:http://dx.doi.org/10.1002/humu.1380050313
- ↑ Kaul R, Gao GP, Matalon R, Aloya M, Su Q, Jin M, Johnson AB, Schutgens RB, Clarke JT. Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease. Am J Hum Genet. 1996 Jul;59(1):95-102. PMID:8659549
- ↑ Kobayashi K, Tsujino S, Ezoe T, Hamaguchi H, Nihei K, Sakuragawa N. Missense mutation (I143T) in a Japanese patient with Canavan disease. Hum Mutat. 1998;Suppl 1:S308-9. PMID:9452117
- ↑ Rady PL, Vargas T, Tyring SK, Matalon R, Langenbeck U. Novel missense mutation (Y231C) in a turkish patient with canavan disease. Am J Med Genet. 1999 Nov 26;87(3):273-5. PMID:10564886
- ↑ Elpeleg ON, Shaag A. The spectrum of mutations of the aspartoacylase gene in Canavan disease in non-Jewish patients. J Inherit Metab Dis. 1999 Jun;22(4):531-4. PMID:10407784
- ↑ Sistermans EA, de Coo RF, van Beerendonk HM, Poll-The BT, Kleijer WJ, van Oost BA. Mutation detection in the aspartoacylase gene in 17 patients with Canavan disease: four new mutations in the non-Jewish population. Eur J Hum Genet. 2000 Jul;8(7):557-60. PMID:10909858 doi:10.1038/sj.ejhg.5200477
- ↑ Zeng BJ, Wang ZH, Ribeiro LA, Leone P, De Gasperi R, Kim SJ, Raghavan S, Ong E, Pastores GM, Kolodny EH. Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease. J Inherit Metab Dis. 2002 Nov;25(7):557-70. PMID:12638939
- ↑ Olsen TR, Tranebjaerg L, Kvittingen EA, Hagenfeldt L, Moller C, Nilssen O. Two novel aspartoacylase gene (ASPA) missense mutations specific to Norwegian and Swedish patients with Canavan disease. J Med Genet. 2002 Sep;39(9):e55. PMID:12205125
- ↑ Bitto E, Bingman CA, Wesenberg GE, McCoy JG, Phillips GN Jr. Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):456-61. Epub 2006 Dec 28. PMID:17194761
|
