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Physical evidence supporting a ribosomal shunting mechanism of translation initiation for BACE1 mRNA

In Alzheimer disease, elevated levels of the BACE1 enzyme are correlated with increased production of amyloid peptides and disease pathology. The increase in BACE1 levels is post-transcriptional and may involve altered translation efficiency. Earlier studies have indicated that translation of BACE1...

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Autores principales: Koh, Dora C., Edelman, Gerald M., Mauro, Vincent P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718059/
https://www.ncbi.nlm.nih.gov/pubmed/26824018
http://dx.doi.org/10.4161/trla.24400
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author Koh, Dora C.
Edelman, Gerald M.
Mauro, Vincent P.
author_facet Koh, Dora C.
Edelman, Gerald M.
Mauro, Vincent P.
author_sort Koh, Dora C.
collection PubMed
description In Alzheimer disease, elevated levels of the BACE1 enzyme are correlated with increased production of amyloid peptides and disease pathology. The increase in BACE1 levels is post-transcriptional and may involve altered translation efficiency. Earlier studies have indicated that translation of BACE1 mRNA is cap-dependent. As ribosomal subunits move from the cap-structure to the initiation codon, they fail to recognize several AUG codons in the 5′ leader. In this study, we looked for physical evidence of the mechanism underlying ribosomal scanning or shunting along the BACE1 5′ leader by investigating structural stability in the 5′ leaders of endogenous mRNAs in vivo. To perform this analysis, we probed RNAs using lead(II) acetate, a cell-permeable chemical that induces cleavage of unpaired nucleotides having conformational flexibility. The data revealed that the ≈440-nt 5′ leader was generally resistant to cleavage except for a region upstream of the initiation codon. Cleavage continued into the coding region, consistent with destabilization of secondary structures by translating ribosomes. Evidence that a large segment of the BACE1 5′ leader was not cleaved indicates that this region is structurally stable and suggests that it is not scanned. The data support a mechanism of translation initiation in which ribosomal subunits bypass (shunt) part of the BACE1 5′ leader to reach the initiation codon. We suggest that a nucleotide bias in the 5′ leader may predispose the initiation codon to be more accessible than other AUG codons in the 5′ leader, leading to an increase in its relative utilization.
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spelling pubmed-47180592016-01-28 Physical evidence supporting a ribosomal shunting mechanism of translation initiation for BACE1 mRNA Koh, Dora C. Edelman, Gerald M. Mauro, Vincent P. Translation (Austin) Research Paper In Alzheimer disease, elevated levels of the BACE1 enzyme are correlated with increased production of amyloid peptides and disease pathology. The increase in BACE1 levels is post-transcriptional and may involve altered translation efficiency. Earlier studies have indicated that translation of BACE1 mRNA is cap-dependent. As ribosomal subunits move from the cap-structure to the initiation codon, they fail to recognize several AUG codons in the 5′ leader. In this study, we looked for physical evidence of the mechanism underlying ribosomal scanning or shunting along the BACE1 5′ leader by investigating structural stability in the 5′ leaders of endogenous mRNAs in vivo. To perform this analysis, we probed RNAs using lead(II) acetate, a cell-permeable chemical that induces cleavage of unpaired nucleotides having conformational flexibility. The data revealed that the ≈440-nt 5′ leader was generally resistant to cleavage except for a region upstream of the initiation codon. Cleavage continued into the coding region, consistent with destabilization of secondary structures by translating ribosomes. Evidence that a large segment of the BACE1 5′ leader was not cleaved indicates that this region is structurally stable and suggests that it is not scanned. The data support a mechanism of translation initiation in which ribosomal subunits bypass (shunt) part of the BACE1 5′ leader to reach the initiation codon. We suggest that a nucleotide bias in the 5′ leader may predispose the initiation codon to be more accessible than other AUG codons in the 5′ leader, leading to an increase in its relative utilization. Taylor & Francis 2013-04-01 /pmc/articles/PMC4718059/ /pubmed/26824018 http://dx.doi.org/10.4161/trla.24400 Text en Copyright © 2013 Landes Bioscience http://creativecommons.org/licenses/by-nc/3.0/ This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
spellingShingle Research Paper
Koh, Dora C.
Edelman, Gerald M.
Mauro, Vincent P.
Physical evidence supporting a ribosomal shunting mechanism of translation initiation for BACE1 mRNA
title Physical evidence supporting a ribosomal shunting mechanism of translation initiation for BACE1 mRNA
title_full Physical evidence supporting a ribosomal shunting mechanism of translation initiation for BACE1 mRNA
title_fullStr Physical evidence supporting a ribosomal shunting mechanism of translation initiation for BACE1 mRNA
title_full_unstemmed Physical evidence supporting a ribosomal shunting mechanism of translation initiation for BACE1 mRNA
title_short Physical evidence supporting a ribosomal shunting mechanism of translation initiation for BACE1 mRNA
title_sort physical evidence supporting a ribosomal shunting mechanism of translation initiation for bace1 mrna
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718059/
https://www.ncbi.nlm.nih.gov/pubmed/26824018
http://dx.doi.org/10.4161/trla.24400
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