1e33

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{{STRUCTURE_1e33| PDB=1e33 | SCENE= }}
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==CRYSTAL STRUCTURE OF AN ARYLSULFATASE A MUTANT P426L==
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===CRYSTAL STRUCTURE OF AN ARYLSULFATASE A MUTANT P426L===
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<StructureSection load='1e33' size='340' side='right' caption='[[1e33]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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{{ABSTRACT_PUBMED_11777924}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1e33]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1E33 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1E33 FirstGlance]. <br>
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==Disease==
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NDG:2-(ACETYLAMINO)-2-DEOXY-A-D-GLUCOPYRANOSE'>NDG</scene><br>
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[[http://www.uniprot.org/uniprot/ARSA_HUMAN ARSA_HUMAN]] Defects in ARSA are a cause of leukodystrophy metachromatic (MLD) [MIM:[http://omim.org/entry/250100 250100]]. MLD is a disease due to a lysosomal storage defect. It is characterized by intralysosomal storage of cerebroside-3-sulfate in neural and non-neural tissues, with a diffuse loss of myelin in the central nervous system. Progressive demyelination causes a variety of neurological symptoms, including gait disturbances, ataxias, optical atrophy, dementia, seizures, and spastic tetraparesis. Three forms of the disease can be distinguished according to the age at onset: late-infantile, juvenile and adult.<ref>PMID:1673291</ref><ref>PMID:1678251</ref><ref>PMID:1670590</ref><ref>PMID:1353340</ref><ref>PMID:8101038</ref><ref>PMID:8101083</ref><ref>PMID:8095918</ref><ref>PMID:7902317</ref><ref>PMID:7906588</ref><ref>PMID:8104633</ref><ref>PMID:7909527</ref><ref>PMID:7825603</ref><ref>PMID:7860068</ref><ref>PMID:7581401</ref><ref>PMID:8891236</ref><ref>PMID:9272717</ref><ref>PMID:9090526</ref><ref>PMID:9490297</ref><ref>PMID:9600244</ref><ref>PMID:9452102</ref><ref>PMID:9819708</ref><ref>PMID:10220151</ref><ref>PMID:10477432</ref><ref>PMID:10533072</ref><ref>PMID:10381328</ref><ref>PMID:10751093</ref><ref>PMID:11061266</ref><ref>PMID:11020646</ref><ref>PMID:11456299</ref><ref>PMID:11941485</ref><ref>PMID:12503099</ref><ref>PMID:12788103</ref><ref>PMID:14517960</ref><ref>PMID:14680985</ref><ref>PMID:15326627</ref><ref>PMID:15026521</ref><ref>PMID:15710861</ref><ref>PMID:18693274</ref><ref>PMID:19606494</ref><ref>PMID:20339381</ref><ref>PMID:21265945</ref> Arylsulfatase A activity is defective in multiple sulfatase deficiency (MSD) [MIM:[http://omim.org/entry/272200 272200]]. A clinically and biochemically heterogeneous disorder caused by the simultaneous impairment of all sulfatases, due to defective post-translational modification and activation. It combines features of individual sulfatase deficiencies such as metachromatic leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus, ichthyosis, neurologic deterioration and developmental delay. Note=Arylsulfatase A activity is impaired in multiple sulfatase deficiency due to mutations in SUMF1. SUMF1 mutations result in defective post-translational modification of ARSA at residue Cys-69 that is not converted to 3-oxoalanine.<ref>PMID:7628016</ref><ref>PMID:15146462</ref>
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<tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DDZ:3,3-DIHYDROXY+L-ALANINE'>DDZ</scene></td></tr>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1auk|1auk]], [[1e3c|1e3c]], [[1e2s|1e2s]]</td></tr>
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==Function==
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<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cerebroside-sulfatase Cerebroside-sulfatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.6.8 3.1.6.8] </span></td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1e33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e33 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1e33 RCSB], [http://www.ebi.ac.uk/pdbsum/1e33 PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/ARSA_HUMAN ARSA_HUMAN]] Defects in ARSA are a cause of leukodystrophy metachromatic (MLD) [MIM:[http://omim.org/entry/250100 250100]]. MLD is a disease due to a lysosomal storage defect. It is characterized by intralysosomal storage of cerebroside-3-sulfate in neural and non-neural tissues, with a diffuse loss of myelin in the central nervous system. Progressive demyelination causes a variety of neurological symptoms, including gait disturbances, ataxias, optical atrophy, dementia, seizures, and spastic tetraparesis. Three forms of the disease can be distinguished according to the age at onset: late-infantile, juvenile and adult.<ref>PMID:1673291</ref> <ref>PMID:1678251</ref> <ref>PMID:1670590</ref> <ref>PMID:1353340</ref> <ref>PMID:8101038</ref> <ref>PMID:8101083</ref> <ref>PMID:8095918</ref> <ref>PMID:7902317</ref> <ref>PMID:7906588</ref> <ref>PMID:8104633</ref> <ref>PMID:7909527</ref> <ref>PMID:7825603</ref> <ref>PMID:7860068</ref> <ref>PMID:7581401</ref> <ref>PMID:8891236</ref> <ref>PMID:9272717</ref> <ref>PMID:9090526</ref> <ref>PMID:9490297</ref> <ref>PMID:9600244</ref> <ref>PMID:9452102</ref> <ref>PMID:9819708</ref> <ref>PMID:10220151</ref> <ref>PMID:10477432</ref> <ref>PMID:10533072</ref> <ref>PMID:10381328</ref> <ref>PMID:10751093</ref> <ref>PMID:11061266</ref> <ref>PMID:11020646</ref> <ref>PMID:11456299</ref> <ref>PMID:11941485</ref> <ref>PMID:12503099</ref> <ref>PMID:12788103</ref> <ref>PMID:14517960</ref> <ref>PMID:14680985</ref> <ref>PMID:15326627</ref> <ref>PMID:15026521</ref> <ref>PMID:15710861</ref> <ref>PMID:18693274</ref> <ref>PMID:19606494</ref> <ref>PMID:20339381</ref> <ref>PMID:21265945</ref> Arylsulfatase A activity is defective in multiple sulfatase deficiency (MSD) [MIM:[http://omim.org/entry/272200 272200]]. A clinically and biochemically heterogeneous disorder caused by the simultaneous impairment of all sulfatases, due to defective post-translational modification and activation. It combines features of individual sulfatase deficiencies such as metachromatic leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus, ichthyosis, neurologic deterioration and developmental delay. Note=Arylsulfatase A activity is impaired in multiple sulfatase deficiency due to mutations in SUMF1. SUMF1 mutations result in defective post-translational modification of ARSA at residue Cys-69 that is not converted to 3-oxoalanine.<ref>PMID:7628016</ref> <ref>PMID:15146462</ref>
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== Function ==
[[http://www.uniprot.org/uniprot/ARSA_HUMAN ARSA_HUMAN]] Hydrolyzes cerebroside sulfate.
[[http://www.uniprot.org/uniprot/ARSA_HUMAN ARSA_HUMAN]] Hydrolyzes cerebroside sulfate.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/e3/1e33_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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In one of the most common mutations causing metachromatic leukodystrophy, the P426L-allele of arylsulfatase A (ASA), the deficiency of ASA results from its instability in lysosomes. Inhibition of lysosomal cysteine proteinases protects the P426L-ASA and restores the sulfatide catabolism in fibroblasts of the patients. P426L-ASA, but not wild type ASA, was cleaved by purified cathepsin L at threonine 421 yielding 54- and 9-kDa fragments. X-ray crystallography at 2.5-A resolution showed that cleavage is not due to a difference in the protein fold that would expose the peptide bond following threonine 421 to proteases. Octamerization, which depends on protonation of Glu-424, was impaired for P426L-ASA. The mutation lowers the pH for the octamer/dimer equilibrium by 0.6 pH units from pH 5.8 to 5.2. A second oligomerization mutant (ASA-A464R) was generated that failed to octamerize even at pH 4.8. A464R-ASA was degraded in lysosomes to catalytically active 54-kDa intermediate. In cathepsin L-deficient fibroblasts, degradation of P426L-ASA and A464R-ASA to the 54-kDa fragment was reduced, while further degradation was blocked. This indicates that defective oligomerization of ASA allows degradation of ASA to a catalytically active 54-kDa intermediate by lysosomal cysteine proteinases, including cathepsin L. Further degradation of the 54-kDa intermediate critically depends on cathepsin L and is modified by the structure of the 9-kDa cleavage product.
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==About this Structure==
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Defective oligomerization of arylsulfatase a as a cause of its instability in lysosomes and metachromatic leukodystrophy.,von Bulow R, Schmidt B, Dierks T, Schwabauer N, Schilling K, Weber E, Uson I, von Figura K J Biol Chem. 2002 Mar 15;277(11):9455-61. Epub 2002 Jan 2. PMID:11777924<ref>PMID:11777924</ref>
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[[1e33]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1E33 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<ref group="xtra">PMID:011777924</ref><references group="xtra"/><references/>
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</div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Cerebroside-sulfatase]]
[[Category: Cerebroside-sulfatase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]

Revision as of 15:05, 29 September 2014

CRYSTAL STRUCTURE OF AN ARYLSULFATASE A MUTANT P426L

1e33, resolution 2.50Å

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