Poster abstracts

Poster number 12 submitted by Nien-Ching Han

Elucidate the mechanism of BMAA misincorporation

Nien-Ching Han (Microbiology, The Ohio State University), Tammy Bullwinkle (Microbiology, The Ohio State University), Michael Ibba (Microbiology, The Ohio State University)

Abstract:

Accurate protein synthesis is crucial for maintaining proteomic integrity. Among the many associated factors involved in cellular translational machinery, a critical point to ensure accurate translation is the correct aminoacylation of tRNA by the correspondent aminoacyl-tRNA synthetase (aaRS). aaRS catalyzes aminoacylation reaction through a two-step process. First, the cognate amino acid is activated in the presence of ATP to form an aminoacyl-adenylate, then the activated amino acid is transferred to the correspondent tRNA. However, due to the structural similarity between many of the free amino acid substrates in the cell, some aaRS will misactivate the wrong amino acid at the first step of their catalytic process. To prevent misaminoacylation, these enzymes utilize distinct proofreading domains that will clear these incorrect substrates. It has been shown that the loss of aaRS quality control can be detrimental due to the accumulation of mistranslated proteins. β-N-methylamino-L-alanine (BMAA), is an excitotoxin that has been associated with neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). BMAA has been found in both seafood and human protein extracts, however, the mechanism by which it accumulates is still largely debated. Here we show for the first time that BMAA is a substrate for aaRS, and can be aminoacylated on to tRNAAla. This finding suggests that the misincorporation of BMAA may contribute to its cellular toxicity.

References:
Dunlop, R. A., Cox, P. A., Banack, S. A., & Rodgers, K. J. (2013). The Non-Protein Amino Acid BMAA Is Misincorporated into Human Proteins in Place of l-Serine Causing Protein Misfolding and Aggregation. PLoS ONE, 8(9), e75376.

Lee, J. W., Beebe, K., Nangle, L. A., Jang, J., Longo-Guess, C. M., Cook, S. A., … Ackerman, S. L. (2006). Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration. Nature, 443(7107), 50–55.

Mohler, K., & Ibba, M. (2017). Translational fidelity and mistranslation in the cellular response to stress. Nature Microbiology, 2(August), 1–9.

Keywords: BMAA, aminoacyl-tRNA synthetase, AlaRS