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Ancestral reconstruction reveals mechanisms of ERK regulatory evolution
Protein kinases are crucial to coordinate cellular decisions and therefore their activities are strictly regulated. Previously we used ancestral reconstruction to determine how CMGC group kinase specificity evolved (Howard et al., 2014). In the present study, we reconstructed ancestral kinases to st...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692128/ https://www.ncbi.nlm.nih.gov/pubmed/31407663 http://dx.doi.org/10.7554/eLife.38805 |
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author | Sang, Dajun Pinglay, Sudarshan Wiewiora, Rafal P Selvan, Myvizhi E Lou, Hua Jane Chodera, John D Turk, Benjamin E Gümüş, Zeynep H Holt, Liam J |
author_facet | Sang, Dajun Pinglay, Sudarshan Wiewiora, Rafal P Selvan, Myvizhi E Lou, Hua Jane Chodera, John D Turk, Benjamin E Gümüş, Zeynep H Holt, Liam J |
author_sort | Sang, Dajun |
collection | PubMed |
description | Protein kinases are crucial to coordinate cellular decisions and therefore their activities are strictly regulated. Previously we used ancestral reconstruction to determine how CMGC group kinase specificity evolved (Howard et al., 2014). In the present study, we reconstructed ancestral kinases to study the evolution of regulation, from the inferred ancestor of CDKs and MAPKs, to modern ERKs. Kinases switched from high to low autophosphorylation activity at the transition to the inferred ancestor of ERKs 1 and 2. Two synergistic amino acid changes were sufficient to induce this change: shortening of the β3-αC loop and mutation of the gatekeeper residue. Restoring these two mutations to their inferred ancestral state led to a loss of dependence of modern ERKs 1 and 2 on the upstream activating kinase MEK in human cells. Our results shed light on the evolutionary mechanisms that led to the tight regulation of a kinase that is central in development and disease. |
format | Online Article Text |
id | pubmed-6692128 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-66921282019-08-16 Ancestral reconstruction reveals mechanisms of ERK regulatory evolution Sang, Dajun Pinglay, Sudarshan Wiewiora, Rafal P Selvan, Myvizhi E Lou, Hua Jane Chodera, John D Turk, Benjamin E Gümüş, Zeynep H Holt, Liam J eLife Biochemistry and Chemical Biology Protein kinases are crucial to coordinate cellular decisions and therefore their activities are strictly regulated. Previously we used ancestral reconstruction to determine how CMGC group kinase specificity evolved (Howard et al., 2014). In the present study, we reconstructed ancestral kinases to study the evolution of regulation, from the inferred ancestor of CDKs and MAPKs, to modern ERKs. Kinases switched from high to low autophosphorylation activity at the transition to the inferred ancestor of ERKs 1 and 2. Two synergistic amino acid changes were sufficient to induce this change: shortening of the β3-αC loop and mutation of the gatekeeper residue. Restoring these two mutations to their inferred ancestral state led to a loss of dependence of modern ERKs 1 and 2 on the upstream activating kinase MEK in human cells. Our results shed light on the evolutionary mechanisms that led to the tight regulation of a kinase that is central in development and disease. eLife Sciences Publications, Ltd 2019-08-13 /pmc/articles/PMC6692128/ /pubmed/31407663 http://dx.doi.org/10.7554/eLife.38805 Text en © 2019, Sang et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Sang, Dajun Pinglay, Sudarshan Wiewiora, Rafal P Selvan, Myvizhi E Lou, Hua Jane Chodera, John D Turk, Benjamin E Gümüş, Zeynep H Holt, Liam J Ancestral reconstruction reveals mechanisms of ERK regulatory evolution |
title | Ancestral reconstruction reveals mechanisms of ERK regulatory evolution |
title_full | Ancestral reconstruction reveals mechanisms of ERK regulatory evolution |
title_fullStr | Ancestral reconstruction reveals mechanisms of ERK regulatory evolution |
title_full_unstemmed | Ancestral reconstruction reveals mechanisms of ERK regulatory evolution |
title_short | Ancestral reconstruction reveals mechanisms of ERK regulatory evolution |
title_sort | ancestral reconstruction reveals mechanisms of erk regulatory evolution |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692128/ https://www.ncbi.nlm.nih.gov/pubmed/31407663 http://dx.doi.org/10.7554/eLife.38805 |
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