1e33: Difference between revisions
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==Crystal structure of an Arylsulfatase A mutant P426L== | |||
<StructureSection load='1e33' size='340' side='right'caption='[[1e33]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
| | == Structural highlights == | ||
<table><tr><td colspan='2'>[[1e33]] is a 1 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=1E33 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1E33 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]] 2.5Å</td></tr> | |||
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DDZ:3,3-DIHYDROXY+L-ALANINE'>DDZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=1e33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e33 OCA], [https://pdbe.org/1e33 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1e33 RCSB], [https://www.ebi.ac.uk/pdbsum/1e33 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1e33 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/ARSA_HUMAN ARSA_HUMAN] Defects in ARSA are a cause of leukodystrophy metachromatic (MLD) [MIM:[https://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:[https://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> | |||
== Function == | |||
== | [https://www.uniprot.org/uniprot/ARSA_HUMAN ARSA_HUMAN] Hydrolyzes cerebroside sulfate. | ||
== 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/e3/1e33_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=1e33 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | 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. | ||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 1e33" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Sulfatase 3D structures|Sulfatase 3D structures]] | |||
[[ | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Dierks T]] | |||
[[Category: Dierks | [[Category: Schmidt B]] | ||
[[Category: Uson I]] | |||
[[Category: Schmidt | [[Category: Von Buelow R]] | ||
[[Category: Uson | [[Category: Von Figura K]] | ||
[[Category: | |||
[[Category: | |||