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Exonic splicing code and protein binding sites for calcium

Auxilliary splicing sequences in exons, known as enhancers (ESEs) and silencers (ESSs), have been subject to strong selection pressures at the RNA and protein level. The protein component of this splicing code is substantial, recently estimated at ∼50% of the total information within ESEs, but remai...

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Autores principales: Pengelly, Reuben J, Bakhtiar, Dara, Borovská, Ivana, Královičová, Jana, Vořechovský, Igor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177970/
https://www.ncbi.nlm.nih.gov/pubmed/35474482
http://dx.doi.org/10.1093/nar/gkac270
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author Pengelly, Reuben J
Bakhtiar, Dara
Borovská, Ivana
Královičová, Jana
Vořechovský, Igor
author_facet Pengelly, Reuben J
Bakhtiar, Dara
Borovská, Ivana
Královičová, Jana
Vořechovský, Igor
author_sort Pengelly, Reuben J
collection PubMed
description Auxilliary splicing sequences in exons, known as enhancers (ESEs) and silencers (ESSs), have been subject to strong selection pressures at the RNA and protein level. The protein component of this splicing code is substantial, recently estimated at ∼50% of the total information within ESEs, but remains poorly understood. The ESE/ESS profiles were previously associated with the Irving-Williams (I-W) stability series for divalent metals, suggesting that the ESE/ESS evolution was shaped by metal binding sites. Here, we have examined splicing activities of exonic sequences that encode protein binding sites for Ca(2+), a weak binder in the I-W affinity order. We found that predicted exon inclusion levels for the EF-hand motifs and for Ca(2+)-binding residues in nonEF-hand proteins were higher than for average exons. For canonical EF-hands, the increase was centred on the EF-hand chelation loop and, in particular, on Ca(2+)-coordinating residues, with a 1>12>3∼5>9 hierarchy in the 12-codon loop consensus and usage bias at codons 1 and 12. The same hierarchy but a lower increase was observed for noncanonical EF-hands, except for S100 proteins. EF-hand loops preferentially accumulated exon splits in two clusters, one located in their N-terminal halves and the other around codon 12. Using splicing assays and published crosslinking and immunoprecipitation data, we identify candidate trans-acting factors that preferentially bind conserved GA-rich motifs encoding negatively charged amino acids in the loops. Together, these data provide evidence for the high capacity of codons for Ca(2+)-coordinating residues to be retained in mature transcripts, facilitating their exon-level expansion during eukaryotic evolution.
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spelling pubmed-91779702022-06-09 Exonic splicing code and protein binding sites for calcium Pengelly, Reuben J Bakhtiar, Dara Borovská, Ivana Královičová, Jana Vořechovský, Igor Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Auxilliary splicing sequences in exons, known as enhancers (ESEs) and silencers (ESSs), have been subject to strong selection pressures at the RNA and protein level. The protein component of this splicing code is substantial, recently estimated at ∼50% of the total information within ESEs, but remains poorly understood. The ESE/ESS profiles were previously associated with the Irving-Williams (I-W) stability series for divalent metals, suggesting that the ESE/ESS evolution was shaped by metal binding sites. Here, we have examined splicing activities of exonic sequences that encode protein binding sites for Ca(2+), a weak binder in the I-W affinity order. We found that predicted exon inclusion levels for the EF-hand motifs and for Ca(2+)-binding residues in nonEF-hand proteins were higher than for average exons. For canonical EF-hands, the increase was centred on the EF-hand chelation loop and, in particular, on Ca(2+)-coordinating residues, with a 1>12>3∼5>9 hierarchy in the 12-codon loop consensus and usage bias at codons 1 and 12. The same hierarchy but a lower increase was observed for noncanonical EF-hands, except for S100 proteins. EF-hand loops preferentially accumulated exon splits in two clusters, one located in their N-terminal halves and the other around codon 12. Using splicing assays and published crosslinking and immunoprecipitation data, we identify candidate trans-acting factors that preferentially bind conserved GA-rich motifs encoding negatively charged amino acids in the loops. Together, these data provide evidence for the high capacity of codons for Ca(2+)-coordinating residues to be retained in mature transcripts, facilitating their exon-level expansion during eukaryotic evolution. Oxford University Press 2022-04-26 /pmc/articles/PMC9177970/ /pubmed/35474482 http://dx.doi.org/10.1093/nar/gkac270 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Gene regulation, Chromatin and Epigenetics
Pengelly, Reuben J
Bakhtiar, Dara
Borovská, Ivana
Královičová, Jana
Vořechovský, Igor
Exonic splicing code and protein binding sites for calcium
title Exonic splicing code and protein binding sites for calcium
title_full Exonic splicing code and protein binding sites for calcium
title_fullStr Exonic splicing code and protein binding sites for calcium
title_full_unstemmed Exonic splicing code and protein binding sites for calcium
title_short Exonic splicing code and protein binding sites for calcium
title_sort exonic splicing code and protein binding sites for calcium
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177970/
https://www.ncbi.nlm.nih.gov/pubmed/35474482
http://dx.doi.org/10.1093/nar/gkac270
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