1e33
From Proteopedia
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|PDB= 1e33 |SIZE=350|CAPTION= <scene name='initialview01'>1e33</scene>, resolution 2.50Å | |PDB= 1e33 |SIZE=350|CAPTION= <scene name='initialview01'>1e33</scene>, resolution 2.50Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=MG:MAGNESIUM ION'>MG</scene> | + | |LIGAND= <scene name='pdbligand=FGL:2-AMINOPROPANEDIOIC+ACID'>FGL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NDG:2-(ACETYLAMINO)-2-DEOXY-A-D-GLUCOPYRANOSE'>NDG</scene> |
| - | |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] | + | |ACTIVITY= <span class='plainlinks'>[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] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1e33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e33 OCA], [http://www.ebi.ac.uk/pdbsum/1e33 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1e33 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==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. | 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:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607574 607574]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Schmidt, B.]] | [[Category: Schmidt, B.]] | ||
[[Category: Uson, I.]] | [[Category: Uson, I.]] | ||
| - | [[Category: MG]] | ||
[[Category: cerebroside-3-sulfate hydrolysis]] | [[Category: cerebroside-3-sulfate hydrolysis]] | ||
[[Category: formylglycine]] | [[Category: formylglycine]] | ||
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[[Category: lysosomal enzyme]] | [[Category: lysosomal enzyme]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 19:54:03 2008'' |
Revision as of 16:54, 30 March 2008
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| , resolution 2.50Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , | ||||||
| Activity: | Cerebroside-sulfatase, with EC number 3.1.6.8 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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
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