1e33

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[[Image:1e33.gif|left|200px]]<br /><applet load="1e33" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:1e33.gif|left|200px]]
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caption="1e33, resolution 2.50&Aring;" />
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'''CRYSTAL STRUCTURE OF AN ARYLSULFATASE A MUTANT P426L'''<br />
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{{Structure
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|PDB= 1e33 |SIZE=350|CAPTION= <scene name='initialview01'>1e33</scene>, resolution 2.50&Aring;
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|SITE=
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|LIGAND= <scene name='pdbligand=MG:MAGNESIUM ION'>MG</scene>
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|ACTIVITY= [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]
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|GENE=
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}}
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'''CRYSTAL STRUCTURE OF AN ARYLSULFATASE A MUTANT P426L'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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1E33 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=MG:'>MG</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1E33 OCA].
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1E33 is a [[Single protein]] structure of 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].
==Reference==
==Reference==
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11777924 11777924]
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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:[http://www.ncbi.nlm.nih.gov/pubmed/11777924 11777924]
[[Category: Cerebroside-sulfatase]]
[[Category: Cerebroside-sulfatase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: lysosomal enzyme]]
[[Category: lysosomal enzyme]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:23:15 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 10:48:47 2008''

Revision as of 08:48, 20 March 2008


PDB ID 1e33

Drag the structure with the mouse to rotate
, resolution 2.50Å
Ligands:
Activity: Cerebroside-sulfatase, with EC number 3.1.6.8
Coordinates: save as pdb, mmCIF, xml



CRYSTAL STRUCTURE OF AN ARYLSULFATASE A MUTANT P426L


Contents

Overview

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.

Disease

Known disease associated with this structure: Metachromatic leukodystrophy OMIM:[607574]

About this Structure

1E33 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

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

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