5V2I

Crystal structure of a mutant glycosylasparaginase (G172D) that causes the genetic disease Aspartylglucosaminuria

5V2I の概要

• エントリーDOI: 10.2210/pdb5v2i/pdb
• 分子名称: Glycosylasparaginase (2 entities in total)
• 機能のキーワード: beta-aha, catalytic mechanism, hydrolase
• 由来する生物種: Elizabethkingia meningoseptica
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64475.34

構造登録者

Pande, S.,Guo, H. (登録日: 2017-03-04, 公開日: 2017-05-17, 最終更新日: 2023-10-04)

主引用文献

Pande, S.,Lakshminarasimhan, D.,Guo, H.C.
Crystal structure of a mutant glycosylasparaginase shedding light on aspartylglycosaminuria-causing mechanism as well as on hydrolysis of non-chitobiose substrate.
Mol. Genet. Metab., 121:150-156, 2017

PubMed Abstract: Glycosylasparaginase (GA) is an amidase that cleaves Asn-linked glycoproteins in lysosomes. Deficiency of this enzyme causes accumulation of glycoasparagines in lysosomes of cells, resulting in a genetic condition called aspartylglycosaminuria (AGU). To better understand the mechanism of a disease-causing mutation with a single residue change from a glycine to an aspartic acid, we generated a model mutant enzyme at the corresponding position (named G172D mutant). Here we report a 1.8Å resolution crystal structure of mature G172D mutant and analyzed the reason behind its low hydrolase activity. Comparison of mature G172D and wildtype GA models reveals that the presence of Asp 172 near the catalytic site affects substrate catabolism in mature G172D, making it less efficient in substrate processing. Also recent studies suggest that GA is capable of processing substrates that lack a chitobiose (Glycan, N-acetylchiobios, NAcGlc) moiety, by its exo-hydrolase activity. The mechanism for this type of catalysis is not yet clear. l-Aspartic acid β-hydroxamate (β-AHA) is a non-chitobiose substrate that is known to interact with GA. To study the underlying mechanism of non-chitobiose substrate processing, we built a GA-β-AHA complex structure by comparing to a previously published G172D mutant precursor in complex with a β-AHA molecule. A hydrolysis mechanism of β-AHA by GA is proposed based on this complex model.

PubMed: 28457719
DOI: 10.1016/j.ymgme.2017.04.008

実験手法

X-RAY DIFFRACTION (1.83 Å)