Incorporation of the neurotoxin β-Methylamino-L-alanine in SOD1 promotes protein misfolding and suggests a role in ALS etiology


Identification: Proctor, Elizabeth


Description

Incorporation of the neurotoxin β-Methylamino-L-alanine in SOD1 promotes protein misfolding and suggests a role in ALS etiology
 
Elizabeth A. Proctor1, David D. Mowrey2, Nikolay V. Dokholyan2
1Department of Biological Engineering, Massachusetts Institute of Technology; 2Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill
      
Exposure to the environmental toxin β-methylamino-L-alanine (BMAA) is linked to some sporadic cases of amyotrophic lateral sclerosis (ALS), but the mechanism by which it promotes disease remains unknown. We propose that incorporation of BMAA into the ALS-linked protein Cu,Zn superoxide dismutase (SOD1) in place of serine upon translation promotes protein misfolding and aggregation, which has been linked to ALS onset and progression. Using molecular simulation and predictive energetic computation, we demonstrate that substituting any serine with BMAA in SOD1 results in structural destabilization. Incorporation at serine 107 induces aberrant dynamics and structural strain at the metal-binding sites, promoting neurotoxic SOD1 aggregation. We propose that translational incorporation of BMAA into SOD1 is directly responsible for its toxicity in motor neurons, and that BMAA modification of SOD1 may serve as a biomarker of ALS.
 

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