View source for 2i3c


==Crystal Structure of an Aspartoacylase from Homo Sapiens==
<StructureSection load='2i3c' size='340' side='right'caption='[[2i3c]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</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='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>
</table>
== Disease ==
[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 ==
[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 ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <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>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=2i3c ConSurf].
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== 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<ref>PMID:17194761</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2i3c" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aminoacylase 3D structures|Aminoacylase 3D structures]]
*[[Aspartoacylase 3D structures|Aspartoacylase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bingman CA]]
[[Category: Bitto E]]
[[Category: Mccoy JG]]
[[Category: Phillips Jr GN]]
[[Category: Wesenberg GE]]