Mechanistic insights into the loss-of-function mechanisms of rare human D-amino acid oxidase variants implicated in amyotrophic lateral sclerosis.

ABSTRACT: Impaired enzymatic activity in D-amino acid oxidase (DAAO) caused by missense mutations has been shown to trigger amyotrophic lateral sclerosis (ALS) through an abnormal accumulation of D-serine in the spinal cord. While loss of enzymatic functions of certain ALS-causing DAAO variants have been studied before, a detailed understanding of structure-dynamics-function relationship of the rare DAAO variants has not been investigated hitherto. To address this, we carried out a comprehensive study of all the reported rare DAAO variants. By employing a spectrum of bioinformatics analyses along with extensive structural dynamics simulations, we show that certain rare variants disrupted key interactions with the active site and decreased the conformational flexibility of active site loop comprising

SUBMITTER: Padhi AK 

PROVIDER: S-EPMC7555490 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature