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Cited by 23Genomics and Phylogenetic StudiesReceptor Mechanisms and SignalingProtein Structure and Dynamics

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Remote homolog detection places insect chemoreceptors in a cryptic protein superfamily spanning the tree of life

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Himmel, Nathaniel J., Moi, David, Benton, Richard·2023·Current Biology
DOI 10.1016/j.cub.2023.10.008

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Abstract

Many proteins exist in the so-called "twilight zone" of sequence alignment, where low pairwise sequence identity makes it difficult to determine homology and phylogeny.1,2 As protein tertiary structure is often more conserved,3 recent advances in ab initio protein folding have made structure-based identification of putative homologs feasible.4,5,6 We present a pipeline for the identification and characterization of distant homologs and apply it to 7-transmembrane-domain ion channels (7TMICs), a protein group founded by insect odorant and gustatory receptors. Previous sequence and limited structure-based searches identified putatively related proteins, mainly in other animals and plants.7,8,9,10 However, very few 7TMICs have been identified in non-animal, non-plant taxa. Moreover, these proteins' remarkable sequence dissimilarity made it uncertain whether disparate 7TMIC types (Gr/Or, Grl, GRL, DUF3537, PHTF, and GrlHz) are homologous or convergent, leaving their evolutionary history unresolved. Our pipeline identified thousands of new 7TMICs in archaea, bacteria, and unicellular eukaryotes. Using graph-based analyses and protein language models to extract family-wide signatures, we demonstrate that 7TMICs have structure and sequence similarity, supporting homology. Through sequence- and structure-based phylogenetics, we classify eukaryotic 7TMICs into two families (Class-A and Class-B), which are the result of a gene duplication predating the split(s) leading to Amorphea (animals, fungi, and allies) and Diaphoretickes (plants and allies). Our work reveals 7TMICs as a cryptic superfamily, with origins close to the evolution of cellular life. More generally, this study serves as a methodological proof of principle for the identification of extremely distant protein homologs.

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Research works printed but not linked: 66

  1. Rost, 1997, Protein structures sustain evolutionary drift, Fold. Des., 2, S19, 10.1016/S1359-0278(97)00059-X · DOI
  2. Illergård, 2009, Structure is three to ten times more conserved than sequence—A study of structural response in protein cores, Proteins, 77, 499, 10.1002/prot.22458 · DOI
  3. Varadi, 2022, AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models, Nucleic Acids Res., 50, D439, 10.1093/nar/gkab1061 · DOI · Paper page
  4. Benton, 2015, Multigene family evolution: perspectives from insect chemoreceptors, Trends Ecol. Evol., 30, 590, 10.1016/j.tree.2015.07.009 · DOI
  5. Benton, 2020, A putative origin of the insect chemosensory receptor superfamily in the last common eukaryotic ancestor, eLife, 9, 10.7554/eLife.62507 · DOI
  6. Robertson, 2015, The insect chemoreceptor superfamily is ancient in animals, Chem. Senses, 40, 609, 10.1093/chemse/bjv046 · DOI
  7. Benton, 2023, Structural screens identify candidate human homologs of insect chemoreceptors and cryptic Drosophila gustatory receptor-like proteins, eLife, 12, 10.7554/eLife.85537 · DOI
  8. Joseph, 2015, Drosophila chemoreceptors: a molecular interface between the chemical world and the brain, Trends Genet., 31, 683, 10.1016/j.tig.2015.09.005 · DOI
  9. Robertson, 2019, Molecular evolution of the major arthropod chemoreceptor gene families, Annu. Rev. Entomol., 64, 227, 10.1146/annurev-ento-020117-043322 · DOI
  10. Clyne, 1999, A novel family of divergent seven-transmembrane proteins: candidate odorant receptors in Drosophila, Neuron, 22, 327, 10.1016/S0896-6273(00)81093-4 · DOI · Paper page
  11. Clyne, 2000, Candidate taste receptors in Drosophila, Science, 287, 1830, 10.1126/science.287.5459.1830 · DOI
  12. Gao, 1999, Identification of candidate Drosophila olfactory receptors from genomic DNA sequence, Genomics, 60, 31, 10.1006/geno.1999.5894 · DOI
  13. Scott, 2001, A chemosensory gene family encoding candidate gustatory and olfactory receptors in Drosophila, Cell, 104, 661, 10.1016/S0092-8674(01)00263-X · DOI · Paper page
  14. Vosshall, 1999, A spatial map of olfactory receptor expression in the Drosophila antenna, Cell, 96, 725, 10.1016/S0092-8674(00)80582-6 · DOI
  15. Zdobnov, 2002, Comparative genome and proteome analysis of Anopheles gambiae and Drosophila melanogaster, Science, 298, 149, 10.1126/science.1077061 · DOI · Paper page
  16. Saina, 2015, A cnidarian homologue of an insect gustatory receptor functions in developmental body patterning, Nat. Commun., 6, 10.1038/ncomms7243 · DOI
  17. Butterwick, 2018, Cryo-EM structure of the insect olfactory receptor Orco, Nature, 560, 447, 10.1038/s41586-018-0420-8 · DOI
  18. del Mármol, 2021, The structural basis of odorant recognition in insect olfactory receptors, Nature, 597, 126, 10.1038/s41586-021-03794-8 · DOI
  19. Sato, 2008, Insect olfactory receptors are heteromeric ligand-gated ion channels, Nature, 452, 1002, 10.1038/nature06850 · DOI
  20. Wicher, 2008, Drosophila odorant receptors are both ligand-gated and cyclic-nucleotide-activated cation channels, Nature, 452, 1007, 10.1038/nature06861 · DOI
  21. Benton, 2006, Atypical membrane topology and heteromeric function of Drosophila odorant receptors in vivo, PLoS Biol., 4, 10.1371/journal.pbio.0040020 · DOI
  22. Hopf, 2015, Amino acid coevolution reveals three-dimensional structure and functional domains of insect odorant receptors, Nat. Commun., 6, 10.1038/ncomms7077 · DOI
  23. Holm, 2008, Searching protein structure databases with DaliLite v.3, Bioinformatics, 24, 2780, 10.1093/bioinformatics/btn507 · DOI
  24. Holm, 2000, DaliLite workbench for protein structure comparison, Bioinformatics, 16, 566, 10.1093/bioinformatics/16.6.566 · DOI · Paper page
  25. Hallgren, 2022, DeepTMHMM predicts alpha and beta transmembrane proteins using deep neural networks, bioRxiv
  26. Cox, 2008, The archaebacterial origin of eukaryotes, Proc. Natl. Acad. Sci. USA, 105, 20356, 10.1073/pnas.0810647105 · DOI
  27. Eme, 2023, Inference and reconstruction of the heimdallarchaeial ancestry of eukaryotes, Nature, 618, 992, 10.1038/s41586-023-06186-2 · DOI
  28. Liu, 2021, Expanded diversity of Asgard archaea and their relationships with eukaryotes, Nature, 593, 553, 10.1038/s41586-021-03494-3 · DOI
  29. Spang, 2018, Asgard archaea are the closest prokaryotic relatives of eukaryotes, PLoS Genet., 14, 10.1371/journal.pgen.1007080 · DOI
  30. Williams, 2013, An archaeal origin of eukaryotes supports only two primary domains of life, Nature, 504, 231, 10.1038/nature12779 · DOI · Paper page
  31. Altschul, 1997, Gapped BLAST and PSI-BLAST: a new generation of protein database search programs, Nucleic Acids Res., 25, 3389, 10.1093/nar/25.17.3389 · DOI · Paper page
  32. Rozenberg, 2021, Microbial rhodopsins: the last two decades, Annu. Rev. Microbiol., 75, 427, 10.1146/annurev-micro-031721-020452 · DOI
  33. Yeung, 2023, Alignment-free estimation of sequence conservation for identifying functional sites using protein sequence embeddings, Brief. Bioinform., 24, 10.1093/bib/bbac599 · DOI
  34. Krapp, 2023, PeSTo: parameter-free geometric deep learning for accurate prediction of protein binding interfaces, Nat. Commun., 14, 10.1038/s41467-023-37701-8 · DOI
  35. Mirdita, 2017, Uniclust databases of clustered and deeply annotated protein sequences and alignments, Nucleic Acids Res., 45, D170, 10.1093/nar/gkw1081 · DOI
  36. Mirdita, 2019, MMseqs2 desktop and local web server app for fast, interactive sequence searches, Bioinformatics, 35, 2856, 10.1093/bioinformatics/bty1057 · DOI · Paper page
  37. Mirdita, 2022, ColabFold: making Protein folding accessible to all, Nat. Methods, 19, 679, 10.1038/s41592-022-01488-1 · DOI · Paper page
  38. Mitchell, 2020, MGnify: the microbiome analysis resource in 2020, Nucleic Acids Res., 48, D570
  39. Burki, 2020, The new tree of eukaryotes, Trends Ecol. Evol., 35, 43, 10.1016/j.tree.2019.08.008 · DOI · Paper page
  40. Moi, 2023, Structural phylogenetics unravels the evolutionary diversification of communication systems in gram-positive bacteria and their viruses, bioRxiv
  41. Larusso, 2008, Type II opsins: evolutionary origin by internal domain duplication?, J. Mol. Evol., 66, 417, 10.1007/s00239-008-9076-6 · DOI
  42. Benton, 2022, Drosophila olfaction: past, present and future, Proc. Biol. Sci., 289, 20222054
  43. Chen, 2020, Recent advances in the genetic basis of taste detection in Drosophila, Cell. Mol. Life Sci., 77, 1087, 10.1007/s00018-019-03320-0 · DOI
  44. Paradis, 2019, ape 5.0: an environment for modern phylogenetics and evolutionary analyses in R, Bioinformatics, 35, 526, 10.1093/bioinformatics/bty633 · DOI
  45. Fu, 2012, CD-HIT: accelerated for clustering the next-generation sequencing data, Bioinformatics, 28, 3150, 10.1093/bioinformatics/bts565 · DOI · Paper page
  46. Li, 2006, Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences, Bioinformatics, 22, 1658, 10.1093/bioinformatics/btl158 · DOI
  47. Frickey, 2004, CLANS: a Java application for visualizing protein families based on pairwise similarity, Bioinformatics, 20, 3702, 10.1093/bioinformatics/bth444 · DOI
  48. Gabler, 2020, Protein sequence analysis using the MPI bioinformatics toolkit, Curr. Protoc. Bioinformatics, 72, 10.1002/cpbi.108 · DOI · Paper page
  49. Zimmermann, 2018, A completely reimplemented MPI bioinformatics toolkit with a new HHpred server at its core, J. Mol. Biol., 430, 2237, 10.1016/j.jmb.2017.12.007 · DOI · Paper page
  50. Emsley, 2010, Features and development of Coot, Acta Crystallogr. D Biol. Crystallogr., 66, 486, 10.1107/S0907444910007493 · DOI · Paper page
  51. Shannon, 2003, Cytoscape: A software environment for integrated models of biomolecular interaction networks, Genome Res., 13, 2498, 10.1101/gr.1239303 · DOI · Paper page
  52. Price, 2010, FastTree 2 – Approximately maximum-likelihood trees for large alignments, PLoS One, 5, 10.1371/journal.pone.0009490 · DOI · Paper page
  53. Letunic, 2021, Interactive Tree Of Life (iTOL) v5: an online tool for phylogenetic tree display and annotation, Nucleic Acids Res., 49, W293, 10.1093/nar/gkab301 · DOI
  54. Edgar, 2022, Muscle5: high-accuracy alignment ensembles enable unbiased assessments of sequence homology and phylogeny, Nat. Commun., 13, 10.1038/s41467-022-34630-w · DOI
  55. Käll, 2004, A combined transmembrane topology and signal peptide prediction method, J. Mol. Biol., 338, 1027, 10.1016/j.jmb.2004.03.016 · DOI
  56. Käll, 2007, Advantages of combined transmembrane topology and signal peptide prediction—the Phobius web server, Nucleic Acids Res., 35, W429, 10.1093/nar/gkm256 · DOI
  57. Revell, 2012, phytools: an R package for phylogenetic comparative biology (and other things), Methods Ecol. Evol., 3, 217, 10.1111/j.2041-210X.2011.00169.x · DOI
  58. Aberer, 2013, Pruning rogue taxa improves phylogenetic accuracy: an efficient algorithm and Webservice, Syst. Biol., 62, 162, 10.1093/sysbio/sys078 · DOI
  59. Jombart, 2017, treespace: statistical exploration of landscapes of phylogenetic trees, Mol. Ecol. Resour., 17, 1385, 10.1111/1755-0998.12676 · DOI
  60. Capella-Gutiérrez, 2009, trimAl: a tool for automated alignment trimming in large-scale phylogenetic analyses, Bioinformatics, 25, 1972, 10.1093/bioinformatics/btp348 · DOI
  61. Holm, 2020, Using Dali for protein structure comparison, 29, 10.1007/978-1-0716-0270-6_3 · DOI
  62. Atkinson, 2009, Using sequence similarity networks for visualization of relationships across diverse protein superfamilies, PLoS One, 4, 10.1371/journal.pone.0004345 · DOI
  63. Brand, 2018, The origin of the odorant receptor gene family in insects, eLife, 7, 10.7554/eLife.38340 · DOI
  64. Robertson, 2003, Molecular evolution of the insect chemoreceptor gene superfamily in Drosophila melanogaster, Proc. Natl. Acad. Sci. USA, 100, 14537, 10.1073/pnas.2335847100 · DOI
  65. Bulzu, 2019, Casting light on Asgardarchaeota metabolism in a sunlit microoxic niche, Nat. Microbiol., 4, 1129, 10.1038/s41564-019-0404-y · DOI
  66. Ramirez, 2016, The last common ancestor of most bilaterian animals possessed at least nine opsins, Genome Biol. Evol., 8, 3640

Metadata

Authors
Himmel, N. J., Moi, D., & Benton, R.
Affiliations
University of Lausanne (CH)
Corresponding author
  • Himmel, Nathaniel J.
  • Benton, Richard
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2023-11
Volume
33
Issue
22
Pages
5023-5033.e4
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2023.10.008
OpenAlex
W4388050018
Cited by
23
References
5
Citations by year
2026: 10 · 2025: 7 · 2024: 6
FWCI
2.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion, other-oa)
  • IRIS (submittedVersion)
Funders
  • ERC (833548)
  • European Research Council
  • HFSP (LT-0003/2022L)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (216623, 310030B-185377)
  • Université de Lausanne
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
protein superfamilies, distant homology detection, olfactory receptors, taste receptors, archaea, bacteria, unicellular eukaryotes, protein language models, graph analysis, protein phylogeny, gene duplication, origin of cellular life, convergent evolution
MeSH terms
Amino Acid Sequence, Animals, Archaea, Humans, Phylogeny, Plants, Proteins, Sequence Alignment, Evolution, Molecular

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