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Structural basis of a point mutation that causes the genetic disease AspartylglucosaminuriaStructural basis of a point mutation that causes the genetic disease Aspartylglucosaminuria
Structural highlights
Function[ASPG_ELIMR] Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. Requires that the glycosylated asparagine moiety is not substituted on its N-(R1) and C- (R2) terminus. Publication Abstract from PubMedAspartylglucosaminuria (AGU) is a lysosomal storage disease caused by a metabolic disorder of lysosomes to digest Asn-linked glycoproteins. The specific enzyme linked to AGU is a lysosomal hydrolase called glycosylasparaginase. Crystallographic studies revealed that a surface loop blocks the catalytic center of the mature hydrolase. Autoproteolysis is therefore required to remove this P loop and open up the hydrolase center. Nonetheless, AGU mutations result in misprocessing of their precursors and are deficient in hydrolyzing glycoasparagines. To understand the catalytic and structural consequences of AGU mutations, we have characterized two AGU models, one corresponding to a Finnish allele and the other found in a Canadian family. We also report a 2.1 A resolution structure of the latter AGU model. The current crystallographic study provides a high-resolution structure of an AGU mutant. It reveals substantial conformation changes at the defective autocleavage site of the AGU mutant, which is trapped as an inactive precursor. Structural Basis of a Point Mutation that Causes the Genetic Disease Aspartylglucosaminuria.,Sui L, Lakshminarasimhan D, Pande S, Guo HC Structure. 2014 Dec 2;22(12):1855-61. doi: 10.1016/j.str.2014.09.014. Epub 2014, Nov 13. PMID:25456816[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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