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Structural insights into aspartoacylase deficiency in Canavan disease (769.4)
Author(s) -
Wijayasinghe Yasanandana,
Pavlovsky Alexander,
Viola Ronald
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.769.4
Subject(s) - mutant , missense mutation , enzyme , phenotype , chemical chaperone , chemistry , biochemistry , mutation , biology , gene
Canavan disease (CD) is a fatal neurodegenerative disorder with impaired N‐acetyl‐L‐aspartic acid (NAA) metabolism. This disease is caused by mutations in the ASPA gene, leading to a deficiency in the aspartoacylase (ASPA) enzyme that hydrolyzes NAA in the brain. The majority of the defects are missense mutations found remote from the active site, resulting in decreased stability and activity. To study the possible structural perturbations triggered by these mutations, ASPA mutants associated with different disease severities have been cloned, purified, and crystallized. E285A, one of the most common mutants shows that loss of the hydrogen bond interaction with Asp 285 disturbs the active site architecture leading to altered substrate binding. The loss of a hydrophobic interaction in the F295S mutant leads to a local collapse of the structure, contributing to low protein stability. But K213E, a mutant associated with a mild disease phenotype, has minimal structural differences compare to the native enzyme. Our improved understanding of the structural changes that occur in ASPA mutants will allow the design of small molecule chaperones that could lead to recovery of the activity of this defective enzyme and therefor a treatment therapy for Canavan disease. Grant Funding Source : Supported by Canavan Research Foundation, and Jacob's Cure Organization