4R4Y

Structural basis of a point mutation that causes the genetic disease Aspartylglucosaminuria

Summary for 4R4Y

• Entry DOI: 10.2210/pdb4r4y/pdb
• Descriptor: N(4)-(Beta-N-acetylglucosaminyl)-L-asparaginase, N-hydroxy-L-asparagine (3 entities in total)
• Functional Keywords: agu structure, autoprocessing, glycosylasparaginase, lysosomal storage disease, pre-autoproteolysis trap, hydrolase
• Biological source: Elizabethkingia miricola
• Cellular location: Periplasm: Q47898
• Total number of polymer chains: 2
• Total formula weight: 64623.45

Authors

Sui, L.,Damodharan, L.,Pande, S.,Guo, H.C. (deposition date: 2014-08-20, release date: 2014-12-17, Last modification date: 2024-02-28)

Primary citation

Sui, L.,Lakshminarasimhan, D.,Pande, S.,Guo, H.C.
Structural Basis of a Point Mutation that Causes the Genetic Disease Aspartylglucosaminuria.
Structure, 22:1855-1861, 2014

PubMed Abstract: Aspartylglucosaminuria (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 Å 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.

PubMed: 25456816
DOI: 10.1016/j.str.2014.09.014

Experimental method

X-RAY DIFFRACTION (2.1 Å)