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1e33

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{{STRUCTURE_1e33| PDB=1e33 | SCENE= }}
{{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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==Overview==
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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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(as it appears on PubMed at http://www.pubmed.gov), where 11777924 is the PubMed ID number.
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{{ABSTRACT_PUBMED_11777924}}
==About this Structure==
==About this Structure==
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[[Category: Hydrolase]]
[[Category: Hydrolase]]
[[Category: Lysosomal enzyme]]
[[Category: Lysosomal enzyme]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 00:04:09 2008''

Revision as of 21:04, 30 June 2008

Image:1e33.png

Template:STRUCTURE 1e33

CRYSTAL STRUCTURE OF AN ARYLSULFATASE A MUTANT P426L

Template:ABSTRACT PUBMED 11777924

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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