Evolution of substrate specificity in a retained enzyme driven by gene loss
- Evolution of Metabolic Diversity Laboratory, Mexico
- Argonne National Laboratory, United States
- University of Texas Health Science Cent, United States
- Weizmann Institute of Science, Israel
- University of California, Berkeley, United States
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico
- Centro de Investigación en Matemáticas, Mexico
- University of Texas Health Science Center, United States
Abstract
The connection between gene loss and the functional adaptation of retained proteins is still poorly understood. We apply phylogenomics and metabolic modeling to detect bacterial species that are evolving by gene loss, with the finding that Actinomycetaceae genomes from human cavities are undergoing sizable reductions, including loss of L-histidine and L-tryptophan biosynthesis. We observe that the dual-substrate phosphoribosyl isomerase A or priA gene, at which these pathways converge, appears to coevolve with the occurrence of trp and his genes. Characterization of a dozen PriA homologs shows that these enzymes adapt from bifunctionality in the largest genomes, to a monofunctional, yet not necessarily specialized, inefficient form in genomes undergoing reduction. These functional changes are accomplished via mutations, which result from relaxation of purifying selection, in residues structurally mapped after sequence and X-ray structural analyses. Our results show how gene loss can drive the evolution of substrate specificity from retained enzymes.
Data availability
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The Whole Genome Shotgun (WGS) A. oris MG-1 projectPublicly available at the NCBI Nucleotide (accession no: MAUB00000000).
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Actinomyces oris strain:MG-1 Genome sequencing and assemblyPublicly available at the NCBI BioProject (accession no: PRJNA327886.
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Actinomycetaceae Phylogenomics: Comparative Analysis of ModelsPublicly available, subject to registering an account, at KBase (accession no: ws.17193.obj.1).
Article and author information
Author details
Francisco Barona-Gómez
Funding
Consejo Nacional de Ciencia y Tecnología (132376,179290)
- Ana Lilia Juárez-Vázquez
- Ernesto A Verduzco-Castro
- Julián Santoyo-Flores
- Mauricio Carrillo-Tripp
National Institutes of Health (GM094585)
- Karolina Michalska
- Gyorgy Babnigg
- Michael Endres
- Andrzej Joachimiak
US Department of Energy (DE-AC02-06CH11357)
- Andrzej Joachimiak
- Christopher S Henry
National Science Foundation (1611952)
- Janaka E Edirisinghe
- Christopher S Henry
National Institute of Dental and Craniofacial Research (DE017382)
- Chenggang Wu
- Hung Ton-That
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Evolution of substrate specificity in a retained enzyme driven by gene loss
eLife 6:e22679.
https://doi.org/10.7554/eLife.22679
Further reading
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- Structural Biology and Molecular Biophysics
The SARS-CoV-2 main protease (Mpro or Nsp5) is critical for production of viral proteins during infection and, like many viral proteases, also targets host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 is recognized and cleaved by SARS-CoV-2 Mpro. TRMT1 installs the N2,N2-dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes cellular protein synthesis and redox homeostasis. We find that Mpro can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain. Evolutionary analysis shows the TRMT1 cleavage site is highly conserved in mammals, except in Muroidea, where TRMT1 is likely resistant to cleavage. TRMT1 proteolysis results in reduced tRNA binding and elimination of tRNA methyltransferase activity. We also determined the structure of an Mpro-TRMT1 peptide complex that shows how TRMT1 engages the Mpro active site in an uncommon substrate binding conformation. Finally, enzymology and molecular dynamics simulations indicate that kinetic discrimination occurs during a later step of Mpro-mediated proteolysis following substrate binding. Together, these data provide new insights into substrate recognition by SARS-CoV-2 Mpro that could help guide future antiviral therapeutic development and show how proteolysis of TRMT1 during SARS-CoV-2 infection impairs both TRMT1 tRNA binding and tRNA modification activity to disrupt host translation and potentially impact COVID-19 pathogenesis or phenotypes.
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