Defective oligomerization of arylsulfatase A as a cause of its instability in lysosomes and metachromatic leukodystrophy

Bulow von R, Schmidt B, Dierks T, Schwabauer N, Schilling K, Weber E, Uson I, Figura von K (2002)
JOURNAL OF BIOLOGICAL CHEMISTRY 277(11): 9455-9461.

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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-Angstrom 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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Bulow von R, Schmidt B, Dierks T, et al. Defective oligomerization of arylsulfatase A as a cause of its instability in lysosomes and metachromatic leukodystrophy. JOURNAL OF BIOLOGICAL CHEMISTRY. 2002;277(11):9455-9461.
Bulow von, R., Schmidt, B., Dierks, T., Schwabauer, N., Schilling, K., Weber, E., Uson, I., et al. (2002). Defective oligomerization of arylsulfatase A as a cause of its instability in lysosomes and metachromatic leukodystrophy. JOURNAL OF BIOLOGICAL CHEMISTRY, 277(11), 9455-9461.
Bulow von, R., Schmidt, B., Dierks, T., Schwabauer, N., Schilling, K., Weber, E., Uson, I., and Figura von, K. (2002). Defective oligomerization of arylsulfatase A as a cause of its instability in lysosomes and metachromatic leukodystrophy. JOURNAL OF BIOLOGICAL CHEMISTRY 277, 9455-9461.
Bulow von, R., et al., 2002. Defective oligomerization of arylsulfatase A as a cause of its instability in lysosomes and metachromatic leukodystrophy. JOURNAL OF BIOLOGICAL CHEMISTRY, 277(11), p 9455-9461.
R. Bulow von, et al., “Defective oligomerization of arylsulfatase A as a cause of its instability in lysosomes and metachromatic leukodystrophy”, JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 277, 2002, pp. 9455-9461.
Bulow von, R., Schmidt, B., Dierks, T., Schwabauer, N., Schilling, K., Weber, E., Uson, I., Figura von, K.: Defective oligomerization of arylsulfatase A as a cause of its instability in lysosomes and metachromatic leukodystrophy. JOURNAL OF BIOLOGICAL CHEMISTRY. 277, 9455-9461 (2002).
Bulow von, R, Schmidt, B, Dierks, Thomas, Schwabauer, N, Schilling, K, Weber, E, Uson, I, and Figura von, K. “Defective oligomerization of arylsulfatase A as a cause of its instability in lysosomes and metachromatic leukodystrophy”. JOURNAL OF BIOLOGICAL CHEMISTRY 277.11 (2002): 9455-9461.
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