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| - | [[Image:1e33.gif|left|200px]] | + | {{Seed}} |
| | + | [[Image:1e33.png|left|200px]] |
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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'''
| + | ===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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_11777924}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 11777924 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_11777924}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Hydrolase]] | | [[Category: Hydrolase]] |
| | [[Category: Lysosomal enzyme]] | | [[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 Tue Jul 1 00:04:09 2008'' |
Revision as of 21:04, 30 June 2008
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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