1e33
From Proteopedia
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'''CRYSTAL STRUCTURE OF AN ARYLSULFATASE A MUTANT P426L''' | '''CRYSTAL STRUCTURE OF AN ARYLSULFATASE A MUTANT P426L''' | ||
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[[Category: Schmidt, B.]] | [[Category: Schmidt, B.]] | ||
[[Category: Uson, I.]] | [[Category: Uson, I.]] | ||
| - | [[Category: | + | [[Category: Cerebroside-3-sulfate hydrolysis]] |
| - | [[Category: | + | [[Category: Formylglycine]] |
| - | [[Category: | + | [[Category: Hydrolase]] |
| - | [[Category: | + | [[Category: Lysosomal enzyme]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 14:35:56 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 11:35, 2 May 2008
CRYSTAL STRUCTURE OF AN ARYLSULFATASE A MUTANT P426L
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.
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 Page seeded by OCA on Fri May 2 14:35:56 2008
