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Native Ubiquitin Structural Changes Resulting from Complexation with β-methylamino-L-alanine (BMAA)

preprint
submitted on 23.09.2020 and posted on 24.09.2020 by Katie Mae Wilson, Aurora Burkus-Matesevac, Samuel Maddox, Christopher Chouinard
β-methylamino-L-alanine (BMAA) has been linked to the development of neurodegenerative (ND) symptoms following chronic environmental exposure through water and dietary sources. The brains of those affected by this condition, often referred to as amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), have exhibited the presence of plaques and neurofibrillary tangles (NFTs) from protein aggregation. Although numerous studies have sought to better understand the correlation between BMAA exposure and onset of ND symptoms, no definitive link has been identified. One prevailing hypothesis is that BMAA acts a small molecule ligand, complexing with critical proteins in the brain and reducing their function. The objective of this research was to investigate the effects of BMAA exposure on the native structure of ubiquitin. We hypothesized that formation of a Ubiquitin+BMAA noncovalent complex would alter the protein’s structure and folding and ultimately affect the ubiquitinproteasome system (UPS) and the unfolded protein response (UPR). Ion mobility-mass spectrometry revealed that at sufficiently high concentrations BMAA did in fact form a noncovalent complex with ubiquitin, however similar complexes were identified for a range of additional amino acids. Collision induced unfolding (CIU) was used to interrogate the unfolding dynamics of native ubiquitin and these Ubq-amino acid complexes and it was determined that complexation with BMAA led to a significant alteration in native protein size and conformation, and this complex required considerably more energy to unfold. This indicates that the complex remains more stable under native conditions and this may indicate that BMAA has attached to a critical binding location.

Funding

Florida Institute of Technology Startup Funds

Agilent Technologies Global Academic Research Support Program #2624930

History

Email Address of Submitting Author

cchouinard@fit.edu

Institution

Florida Institute of Technology

Country

United States

ORCID For Submitting Author

0000-0002-1416-1812

Declaration of Conflict of Interest

The authors declare no competing financial interests.

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