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 residues 216–228, which is essential for substrate binding and product release. Moreover, these variants lost crucial interactions with the cofactor flavin-adenine-dinucleotide, resulting in weaker binding affinity. A detailed inspection revealed that these variants exhibited such characteristics due to the abrogation of specific salt bridges. Taken together, our study provides a gateway into the structural-dynamic features of the rare DAAO variants and highlights the importance of informatics-based integrated analyses in the screening and prioritization of variants a priori to the clinical-functional characterization.
Highlights
amyotrophic lateral sclerosis (ALS), known as motor neurone disease, is a fatal and progressive neurodegenerative disease that causes the death of neurons controlling voluntary muscles and eventually leads to paralysis and death of patients within 3–5 years of disease o nset[1]
Because compromised enzymatic activity of D-amino acid oxidase (DAAO) happens to play a vital role in manifestation of ALS, as a result of excessive accumulation of D-serine, we recently demonstrated that certain structural and dynamic changes disrupts the enzymatic activity in ALS associated DAAO variants, leading to the disease causation[23]
We carried out a comprehensive analysis of all the Project MinE catalogued DAAO rare variants to examine the structural and dynamic changes related to the enzymatic activity and subsequently ALS association
Summary
ALS, known as motor neurone disease, is a fatal and progressive neurodegenerative disease that causes the death of neurons controlling voluntary muscles and eventually leads to paralysis and death of patients within 3–5 years of disease o nset[1]. As rare variants are known to cause an increased disease risk across diverse populations, their discovery and understanding their structure–function relationship is warranted in order to comprehend the origin and progression of ALS In light of this observation, we focused our study on the rare variants catalogued in the Project MinE consortium, whose goal is to sequence the whole genome of > 15,000 ALS patients and ~ 7500 control individuals to provide a comprehensive genetic architecture of ALS12. Because compromised enzymatic activity of DAAO happens to play a vital role in manifestation of ALS, as a result of excessive accumulation of D-serine, we recently demonstrated that certain structural and dynamic changes disrupts the enzymatic activity in ALS associated DAAO variants, leading to the disease causation[23] This encouraged us to investigate if any of the Project MinE derived rare DAAO variants could exhibit loss of enzymatic functions and if so, how and by what molecular mechanisms. This report and our earlier s tudy[23], employing MD simulations and other informatics-based analyses clearly demonstrate that certain Project MinE based rare DAAO variants are loss-of-function type and could cause ALS through an unusual deposition of D-serine in the spinal cord
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