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Resurrection of ancestral effector caspases identifies novel networks for evolution of substrate specificity

Apoptotic caspases evolved with metazoans more than 950 million years ago (MYA), and a series of gene duplications resulted in two subfamilies consisting of initiator and effector caspases. The effector caspase genes (caspases-3, -6, and -7) were subsequently fixed into the Chordata phylum more than...

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Autores principales: Grinshpon, Robert D., Shrestha, Suman, Titus-McQuillan, James, Hamilton, Paul T., Swartz, Paul D., Clark, A. Clay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874516/
https://www.ncbi.nlm.nih.gov/pubmed/31675069
http://dx.doi.org/10.1042/BCJ20190625
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author Grinshpon, Robert D.
Shrestha, Suman
Titus-McQuillan, James
Hamilton, Paul T.
Swartz, Paul D.
Clark, A. Clay
author_facet Grinshpon, Robert D.
Shrestha, Suman
Titus-McQuillan, James
Hamilton, Paul T.
Swartz, Paul D.
Clark, A. Clay
author_sort Grinshpon, Robert D.
collection PubMed
description Apoptotic caspases evolved with metazoans more than 950 million years ago (MYA), and a series of gene duplications resulted in two subfamilies consisting of initiator and effector caspases. The effector caspase genes (caspases-3, -6, and -7) were subsequently fixed into the Chordata phylum more than 650 MYA when the gene for a common ancestor (CA) duplicated, and the three effector caspases have persisted throughout mammalian evolution. All caspases prefer an aspartate residue at the P1 position of substrates, so each caspase evolved discrete cellular roles through changes in substrate recognition at the P4 position combined with allosteric regulation. We examined the evolution of substrate specificity in caspase-6, which prefers valine at the P4 residue, compared with caspases-3 and -7, which prefer aspartate, by reconstructing the CA of effector caspases (AncCP-Ef1) and the CA of caspase-6 (AncCP-6An). We show that AncCP-Ef1 is a promiscuous enzyme with little distinction between Asp, Val, or Leu at P4. The specificity of caspase-6 was defined early in its evolution, where AncCP-6An demonstrates a preference for Val over Asp at P4. Structures of AncCP-Ef1 and of AncCP-6An show a network of charged amino acids near the S4 pocket that, when combined with repositioning a flexible active site loop, resulted in a more hydrophobic binding pocket in AncCP-6An. The ancestral protein reconstructions show that the caspase-hemoglobinase fold has been conserved for over 650 million years and that only three substitutions in the scaffold are necessary to shift substrate selection toward Val over Asp.
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spelling pubmed-68745162019-12-04 Resurrection of ancestral effector caspases identifies novel networks for evolution of substrate specificity Grinshpon, Robert D. Shrestha, Suman Titus-McQuillan, James Hamilton, Paul T. Swartz, Paul D. Clark, A. Clay Biochem J Enzymology Apoptotic caspases evolved with metazoans more than 950 million years ago (MYA), and a series of gene duplications resulted in two subfamilies consisting of initiator and effector caspases. The effector caspase genes (caspases-3, -6, and -7) were subsequently fixed into the Chordata phylum more than 650 MYA when the gene for a common ancestor (CA) duplicated, and the three effector caspases have persisted throughout mammalian evolution. All caspases prefer an aspartate residue at the P1 position of substrates, so each caspase evolved discrete cellular roles through changes in substrate recognition at the P4 position combined with allosteric regulation. We examined the evolution of substrate specificity in caspase-6, which prefers valine at the P4 residue, compared with caspases-3 and -7, which prefer aspartate, by reconstructing the CA of effector caspases (AncCP-Ef1) and the CA of caspase-6 (AncCP-6An). We show that AncCP-Ef1 is a promiscuous enzyme with little distinction between Asp, Val, or Leu at P4. The specificity of caspase-6 was defined early in its evolution, where AncCP-6An demonstrates a preference for Val over Asp at P4. Structures of AncCP-Ef1 and of AncCP-6An show a network of charged amino acids near the S4 pocket that, when combined with repositioning a flexible active site loop, resulted in a more hydrophobic binding pocket in AncCP-6An. The ancestral protein reconstructions show that the caspase-hemoglobinase fold has been conserved for over 650 million years and that only three substitutions in the scaffold are necessary to shift substrate selection toward Val over Asp. Portland Press Ltd. 2019-11-29 2019-11-21 /pmc/articles/PMC6874516/ /pubmed/31675069 http://dx.doi.org/10.1042/BCJ20190625 Text en © 2019 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Enzymology
Grinshpon, Robert D.
Shrestha, Suman
Titus-McQuillan, James
Hamilton, Paul T.
Swartz, Paul D.
Clark, A. Clay
Resurrection of ancestral effector caspases identifies novel networks for evolution of substrate specificity
title Resurrection of ancestral effector caspases identifies novel networks for evolution of substrate specificity
title_full Resurrection of ancestral effector caspases identifies novel networks for evolution of substrate specificity
title_fullStr Resurrection of ancestral effector caspases identifies novel networks for evolution of substrate specificity
title_full_unstemmed Resurrection of ancestral effector caspases identifies novel networks for evolution of substrate specificity
title_short Resurrection of ancestral effector caspases identifies novel networks for evolution of substrate specificity
title_sort resurrection of ancestral effector caspases identifies novel networks for evolution of substrate specificity
topic Enzymology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874516/
https://www.ncbi.nlm.nih.gov/pubmed/31675069
http://dx.doi.org/10.1042/BCJ20190625
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