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Conserved domains and structural motifs that differentiate closely related Rex1 and Rex3 DEDDh exoribonucleases are required for their function in yeast

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Daniels, Peter W., Kelly, Sophie, Tebbs, Iwan J., Mitchell, Phil·2025·PLOS One
DOI 10.1371/journal.pone.0321120PMC PMC12129344

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Abstract

The DEDD family of exonucleases has expanded through evolution whilst retaining a conserved catalytic domain. One subgroup with closely related catalytic DEDD domain sequences includes the yeast enzymes Rex1 (RNA exonuclease 1) and Rex3, the metazoan REXO1 (RNA exonuclease 1 homologue) and Rexo5 proteins, and the plant protein Sdn5 (small RNA degrading nuclease). Comparison of protein structure models and sequence analyses revealed that this group can be differentiated into two distinct clades consisting of Rex1, Rexo5 and Sdn5 on the one hand, and Rex3 and REXO1 on the other. The catalytic domain of Rex1-related proteins is inserted within a conserved, discontinuous alkaline phosphatase (AlkP) domain. The AlkP domain of yeast Rex1 contains three surface loops that are modelled to be directed towards the DEDD domain, one of which forms an extended helical arch that is found in homologues across fungi and plants. We show that this arch and an adjacent loop are required for Rex1-mediated processing of 5S rRNA and tRNA in Saccharomyces cerevisiae . Rex3-related proteins, including REXO1, lack the AlkP domain but contain a KIX domain (CREB kinase-inducible domain (KID) interacting domain) and a cysteine- and histidine-rich domain (CHORD) adjacent to a C-terminal DEDD domain. Deletion of the N-terminal region within yeast Rex3 spanning the KIX domain blocked its function in RNase MRP processing. In contrast to Rex1, Rex3 proteins are found in metazoans and fungi but not in plants or algae. This work identifies evolutionarily conserved structural hallmarks within Rex1 and Rex3 proteins and demonstrates that specific features are required for Rex1- and Rex3-mediated RNA processing pathways in vivo.

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Figures

Fig 1 Rex1 and Rexo5 orthologues have a discontinuous alkaline phosphatase fold. Ribbon structure diagrams of Rex1- and AlkP-related proteins. The central DEDDh and cap domains of Rex1-related proteins and iPGM, respectively, are coloured green; N- and C-terminal portions of AlkP domains are coloured blue and red, respectively. The RRM domains inserted within human Rexo5 are coloured gold. (A) Ribbon structure (residues 53-553) of the yeast Rex1 AF model (AF-P53331). (B) Comparison of the yeast Rex1 AlkP domain with AlkP from E. coli (PDB ID 1ALK) [27]. The perspective shown is towards the surface of the AlkP domain ß-sheet. The Rex1 topology diagram shows the ß-sheet numbering, the insertion points of the DEDDh domain within the AlkP domain and the location of prominent loops. Regions before strand 1, between strands 2 and 3, and connecting strands 3 and 4 within the structure of AlkP, are omitted for clarity. (C) AlkP domain and dual domain structure of iPGM from B. stearothermophilus (PBD ID 1EJJ) [24]. The left-hand panel shows the surface of the ß-sheet, as in panel B. The right-hand panel shows the AlkP and cap domains. (D) Schematic, drawn to scale, of the domain structure of Rex1 and Rexo5 proteins. (E) Ribbon diagram (residues 145-681) of the AF model of fly Rexo5 (AF-Q9VRX7) and the AlkP domain alone, viewed with the perspective shown in panels B and C. (F) AF model of the human Rexo5 protein (AF-Q96IC2, residues 49-774) and the AlkP/RRM module, viewed from the same perspective as shown in panels B, C and E. The inferred 5’-3’ polarity of RNA bound to RRM1 in the human protein is indicated. (G) Predicted aligned error maps and domain schematics of yeast Rex1 and the fly and human Rexo5 proteins.
Fig 1 Rex1 and Rexo5 orthologues have a discontinuous alkaline phosphatase fold. Ribbon structure diagrams of Rex1- and AlkP-related proteins. The central DEDDh and cap domains of Rex1-related proteins and iPGM, respectively, are coloured green; N- and C-terminal portions of AlkP domains are coloured blue and red, respectively. The RRM domains inserted within human Rexo5 are coloured gold. (A) Ribbon structure (residues 53-553) of the yeast Rex1 AF model (AF-P53331). (B) Comparison of the yeast Rex1 AlkP domain with AlkP from E. coli (PDB ID 1ALK) [27]. The perspective shown is towards the surface of the AlkP domain ß-sheet. The Rex1 topology diagram shows the ß-sheet numbering, the insertion points of the DEDDh domain within the AlkP domain and the location of prominent loops. Regions before strand 1, between strands 2 and 3, and connecting strands 3 and 4 within the structure of AlkP, are omitted for clarity. (C) AlkP domain and dual domain structure of iPGM from B. stearothermophilus (PBD ID 1EJJ) [24]. The left-hand panel shows the surface of the ß-sheet, as in panel B. The right-hand panel shows the AlkP and cap domains. (D) Schematic, drawn to scale, of the domain structure of Rex1 and Rexo5 proteins. (E) Ribbon diagram (residues 145-681) of the AF model of fly Rexo5 (AF-Q9VRX7) and the AlkP domain alone, viewed with the perspective shown in panels B and C. (F) AF model of the human Rexo5 protein (AF-Q96IC2, residues 49-774) and the AlkP/RRM module, viewed from the same perspective as shown in panels B, C and E. The inferred 5’-3’ polarity of RNA bound to RRM1 in the human protein is indicated. (G) Predicted aligned error maps and domain schematics of yeast Rex1 and the fly and human Rexo5 proteins.CC BY · PubMed Central
Fig 2 The RRM domains of vertebrate Rexo5 proteins are related to PUF60/FIR. (A) A plot of Dali Z scores for the twin RRMs within the human Rexo5 protein AF model and the most closely related protein structures within the PDB. (B) Structural overlay of the RRM domains in the AF model of human Rexo5 (AF-Q96IC2) and the resolved structure of PUF60 with bound dinucleotide (PDB ID 5KW1) [33]. Z-scores and rmsd values for PUF60 structure overlays with AF models of vertebrate REXO5 proteins are shown.
Fig 2 The RRM domains of vertebrate Rexo5 proteins are related to PUF60/FIR. (A) A plot of Dali Z scores for the twin RRMs within the human Rexo5 protein AF model and the most closely related protein structures within the PDB. (B) Structural overlay of the RRM domains in the AF model of human Rexo5 (AF-Q96IC2) and the resolved structure of PUF60 with bound dinucleotide (PDB ID 5KW1) [33]. Z-scores and rmsd values for PUF60 structure overlays with AF models of vertebrate REXO5 proteins are shown.CC BY · PubMed Central
Fig 3 Surface Loops on the AlkP domain of Rex1 are conserved across fungi. (A) Comparison of the AF model of Rex1 from S. cerevisiae (AF-P53331) (Fig 1A) with homologous proteins from E. nidulans (AF-Q5AVW4), S. pombe (AF-O94443), C. neoformans (AF-A0A225XBF6) and R. irregularis (AF-A0A2I1EHK1). The AlkP and DEDD domains are coloured as in Fig 1. Unstructured N- and C-terminal regions of the protein models are omitted for clarity. The positions of loops 1, 2 and 3 are indicated. (B) Expanded view of the interaction between loop 1 and loop 3 (residues 144-155 and 504-544, respectively) in Rex1 from S. cerevisiae. The positions of key residues are indicated. Dashed lines indicate hydrogen bonding between loops 1 and 3. A structural overlay of loop 1 sequences from the five fungal proteins is included. (C) AF model structure-based sequence alignment of loops 1 and 3. Residues are coloured by conservation.
Fig 3 Surface Loops on the AlkP domain of Rex1 are conserved across fungi. (A) Comparison of the AF model of Rex1 from S. cerevisiae (AF-P53331) (Fig 1A) with homologous proteins from E. nidulans (AF-Q5AVW4), S. pombe (AF-O94443), C. neoformans (AF-A0A225XBF6) and R. irregularis (AF-A0A2I1EHK1). The AlkP and DEDD domains are coloured as in Fig 1. Unstructured N- and C-terminal regions of the protein models are omitted for clarity. The positions of loops 1, 2 and 3 are indicated. (B) Expanded view of the interaction between loop 1 and loop 3 (residues 144-155 and 504-544, respectively) in Rex1 from S. cerevisiae. The positions of key residues are indicated. Dashed lines indicate hydrogen bonding between loops 1 and 3. A structural overlay of loop 1 sequences from the five fungal proteins is included. (C) AF model structure-based sequence alignment of loops 1 and 3. Residues are coloured by conservation.CC BY · PubMed Central
Fig 4 Loops within the AlkP domain of Rex1 are required for RNA processing in vivo. (A) Spot growth assays of rex1∆ rrp47∆ double mutants. Upper panels, growth of a rex1∆ rrp47∆ strain harbouring a plasmid expressing the RRP47 and URA3 genes after transformation with a HIS3 marker plasmid encoding rex1 alleles. Growth on selective medium lacking histidine (SD - His) or containing FOA to purge the URA3 marker plasmid was recorded after 3 days. Lower panel, growth of FOA-resistant isolates on YPD medium. Plates were photographed after 2 days incubation. Assays were performed on three independent isolates. (B) Spot growth assays of randomly selected meiotic progeny from a rex1∆::KANMX4/REX1 rrp47∆::HYGMX4/RRP47 diploid strain harbouring plasmids expressing the wild-type REX1 gene, the loop deletion mutants or the control vector. The panels show growth of haploid progeny on nonselective YPD medium and on medium containing hygromycin and G418. Plates were photographed after incubation for 1-2 days. (C) Western blot analyses of rex1 mutant protein expression levels. Wild-type and mutant rex1 proteins were expressed in a rex1∆ single mutant grown at 30°C. Electrophoretic mobilities of molecular weight markers (size in kDa) are indicated on the left-hand side. of each blot. Rex1 expression levels were normalised to Pgk1. Values for the mean average (av) and mean absolute deviation (mad) of three independent replicates are given. (D) Northern blot hybridisation analyses of total cellular RNA from a wild-type strain, rex1 mutants and the pop1-1 temperature-sensitive mutant. The northern blot was hybridised reiteratively with oligonucleotides complementary to the acceptor stem/3’ trailer sequence boundary of unprocessed tRNAArgUCU, the tRNALysUUU intron and 5S rRNA. Detected tRNA species are indicated schematically on the right. Lines under the schematics indicate the positions of sequences complementary to the oligonucleotide probes used for each panel. The electrophoretic mobilities of 5S rRNA (121 nucleotides), 5.8SS (158 nucleotides) and U24 (89 nucleotides) are indicated as size markers.
Fig 4 Loops within the AlkP domain of Rex1 are required for RNA processing in vivo. (A) Spot growth assays of rex1∆ rrp47∆ double mutants. Upper panels, growth of a rex1∆ rrp47∆ strain harbouring a plasmid expressing the RRP47 and URA3 genes after transformation with a HIS3 marker plasmid encoding rex1 alleles. Growth on selective medium lacking histidine (SD - His) or containing FOA to purge the URA3 marker plasmid was recorded after 3 days. Lower panel, growth of FOA-resistant isolates on YPD medium. Plates were photographed after 2 days incubation. Assays were performed on three independent isolates. (B) Spot growth assays of randomly selected meiotic progeny from a rex1∆::KANMX4/REX1 rrp47∆::HYGMX4/RRP47 diploid strain harbouring plasmids expressing the wild-type REX1 gene, the loop deletion mutants or the control vector. The panels show growth of haploid progeny on nonselective YPD medium and on medium containing hygromycin and G418. Plates were photographed after incubation for 1-2 days. (C) Western blot analyses of rex1 mutant protein expression levels. Wild-type and mutant rex1 proteins were expressed in a rex1∆ single mutant grown at 30°C. Electrophoretic mobilities of molecular weight markers (size in kDa) are indicated on the left-hand side. of each blot. Rex1 expression levels were normalised to Pgk1. Values for the mean average (av) and mean absolute deviation (mad) of three independent replicates are given. (D) Northern blot hybridisation analyses of total cellular RNA from a wild-type strain, rex1 mutants and the pop1-1 temperature-sensitive mutant. The northern blot was hybridised reiteratively with oligonucleotides complementary to the acceptor stem/3’ trailer sequence boundary of unprocessed tRNAArgUCU, the tRNALysUUU intron and 5S rRNA. Detected tRNA species are indicated schematically on the right. Lines under the schematics indicate the positions of sequences complementary to the oligonucleotide probes used for each panel. The electrophoretic mobilities of 5S rRNA (121 nucleotides), 5.8SS (158 nucleotides) and U24 (89 nucleotides) are indicated as size markers.CC BY · PubMed Central
Fig 5 Rex3 related proteins contain KIX and CHORD domains. (A) Structure overlay of AF models for full-length Rex3 (blue) and the DEDDh domain of Rex1 (brown) from S. cerevisiae. Protein domains and the N’- and C’-termini are labelled. (B) Overlay ribbon diagrams of the triple helical domains within yeast Rex3 and human REXO1 proteins and the KIX domains of yeast Med15, mouse CBP and yeast TFIIS. Z-scores and rmsd values for the correlation between Rex3/REXO1 protein structural models and the structures of the KIX domains of Med15 and CBP are given. (C) Structural overlays of the AF models for the CHORD domain of yeast Rex3 (blue) and human REXO1 (red) with the crystal structure of the CHORD domain of RAR1 (purple) [40]. (D) Domain structure of human REXO1 and yeast Rex3 proteins. (E) Structure-based multiple sequence alignments of the KIX and CHORD domains of Rex3 and REOX1 proteins. Residues are coloured by conservation. The KIX domain alignment includes TFIIS, Med15 and CBP.
Fig 5 Rex3 related proteins contain KIX and CHORD domains. (A) Structure overlay of AF models for full-length Rex3 (blue) and the DEDDh domain of Rex1 (brown) from S. cerevisiae. Protein domains and the N’- and C’-termini are labelled. (B) Overlay ribbon diagrams of the triple helical domains within yeast Rex3 and human REXO1 proteins and the KIX domains of yeast Med15, mouse CBP and yeast TFIIS. Z-scores and rmsd values for the correlation between Rex3/REXO1 protein structural models and the structures of the KIX domains of Med15 and CBP are given. (C) Structural overlays of the AF models for the CHORD domain of yeast Rex3 (blue) and human REXO1 (red) with the crystal structure of the CHORD domain of RAR1 (purple) [40]. (D) Domain structure of human REXO1 and yeast Rex3 proteins. (E) Structure-based multiple sequence alignments of the KIX and CHORD domains of Rex3 and REOX1 proteins. Residues are coloured by conservation. The KIX domain alignment includes TFIIS, Med15 and CBP.CC BY · PubMed Central
Fig 6 The N-terminal region of Rex3 is required for processing of RNase MRP RNA. (A) Schematic of the domain architecture of yeast Rex3 and the deletion mutants analysed in this study. (B) Northern blot analyses of RNA from a REX3 wild-type strain, isogenic rex3∆ mutant strains harbouring the cloning vector or expressing either full length, wild-type Rex3 or the deletion mutants, and the pop1-1 mutant during growth at 23°C and 37°C. Total cellular RNA was resolved through 6% polyacrylamide gels, transferred to Hybond N+ membranes and hybridised with a probe specific to the RNase MRP RNA. An SCR1 probe was used as a loading control. (C) Western analyses of whole cell lysates from strains expressing full length Rex3 or the N-terminal deletion mutants. Rex3 expression levels were normalised to Pgk1 and are expressed as a percentage of the wild-type protein. Mean average (av) and mean absolute deviation (mad) values of three independent replicates are given.
Fig 6 The N-terminal region of Rex3 is required for processing of RNase MRP RNA. (A) Schematic of the domain architecture of yeast Rex3 and the deletion mutants analysed in this study. (B) Northern blot analyses of RNA from a REX3 wild-type strain, isogenic rex3∆ mutant strains harbouring the cloning vector or expressing either full length, wild-type Rex3 or the deletion mutants, and the pop1-1 mutant during growth at 23°C and 37°C. Total cellular RNA was resolved through 6% polyacrylamide gels, transferred to Hybond N+ membranes and hybridised with a probe specific to the RNase MRP RNA. An SCR1 probe was used as a loading control. (C) Western analyses of whole cell lysates from strains expressing full length Rex3 or the N-terminal deletion mutants. Rex3 expression levels were normalised to Pgk1 and are expressed as a percentage of the wild-type protein. Mean average (av) and mean absolute deviation (mad) values of three independent replicates are given.CC BY · PubMed Central
Fig 7 Phylogenetic analyses of Rex1 and Rex3 proteins. (A) Phylogenetic tree and multiple sequence alignment of Rex1 and Rex3 proteins. Exo I, II and III motif sequences are shown. The asterisk indicates a conserved Y/F residue in Rex3 proteins. The presence of AlkP, RRM, KIX and CHORD domains within AF structures are indicated to the right (dark blue indicates high confidence pLDDT scores above 70; light blue indicates low confidence pLDDT scores below 70; pink indicates a partial model of high confidence; grey indicates the absence of a model). Domain pLDDT values are given (see also S6 Table). Proteins are identified by their common names or InterPro codes. Organism codes are as follows: TRYB2, T. brucei; STYPI, S. pistillata; 9CHLO, Bathycoccus prasinos; YEAST, S. cerevisiae; EMENI, A. nidulans; 9GLOM, R. irregularis; DICDI, D. discoideum; CRYNV, C. neoformans; SCHPO, S. pombe; TETTS, T. thermophila; STRPU, S. purpuratus; DROME, D. melanogaster; CAEEL, C. elegans; 9TELE, D. translucida; XENLA, X. laevis; AUXPR, A. protothecoides; CHLSO, C. sorokiniana; ORYSJ, O. sativa, subsp. japonica; ARATH, A. thaliana; TOBAC, N. tabacum; KLENI, K. nitens; CHABU, C. braunii; CERRI, C. richardii; MARPO, M. polymorpha; PHYPA, P. patens; EUKA, Planoprotostelium fungivorum; 9FUNG, Umbelopsis vinacea; SPOSA, Sporidiobolus salmonicolor; CAPO3, Capsaspora owczarzaki; 9METZ, Trichoplax sp. H2; TRISP, Trichinella spiralis; HELRO, Helobdella robusta; RAMVA, Ramazzottius varieornatus; 9ANNE, Dimorphilus gyrociliatus; BUGNE, Bugula neritina; SCHHA, Schistosoma haematobium; SCHSO, Schistocephalus solidus; 9BILA, A. steineri; EUMVA, Eumeta variegata; 9EUPU, Arion vulgaris; LINUN, Lingula unguis; ARAVE, Araneus ventricosus; AMPQE, Amphimedon queenslandica; DANRE, D. rerio. (B) Simplified cladogram showing the phylogeny of REX1 and REX3 genes. (C) Structural overlay of AF models for Rex3 from S. cerevisiae and Q9N5W0 from C. elegans. Domains and termini are labelled.
Fig 7 Phylogenetic analyses of Rex1 and Rex3 proteins. (A) Phylogenetic tree and multiple sequence alignment of Rex1 and Rex3 proteins. Exo I, II and III motif sequences are shown. The asterisk indicates a conserved Y/F residue in Rex3 proteins. The presence of AlkP, RRM, KIX and CHORD domains within AF structures are indicated to the right (dark blue indicates high confidence pLDDT scores above 70; light blue indicates low confidence pLDDT scores below 70; pink indicates a partial model of high confidence; grey indicates the absence of a model). Domain pLDDT values are given (see also S6 Table). Proteins are identified by their common names or InterPro codes. Organism codes are as follows: TRYB2, T. brucei; STYPI, S. pistillata; 9CHLO, Bathycoccus prasinos; YEAST, S. cerevisiae; EMENI, A. nidulans; 9GLOM, R. irregularis; DICDI, D. discoideum; CRYNV, C. neoformans; SCHPO, S. pombe; TETTS, T. thermophila; STRPU, S. purpuratus; DROME, D. melanogaster; CAEEL, C. elegans; 9TELE, D. translucida; XENLA, X. laevis; AUXPR, A. protothecoides; CHLSO, C. sorokiniana; ORYSJ, O. sativa, subsp. japonica; ARATH, A. thaliana; TOBAC, N. tabacum; KLENI, K. nitens; CHABU, C. braunii; CERRI, C. richardii; MARPO, M. polymorpha; PHYPA, P. patens; EUKA, Planoprotostelium fungivorum; 9FUNG, Umbelopsis vinacea; SPOSA, Sporidiobolus salmonicolor; CAPO3, Capsaspora owczarzaki; 9METZ, Trichoplax sp. H2; TRISP, Trichinella spiralis; HELRO, Helobdella robusta; RAMVA, Ramazzottius varieornatus; 9ANNE, Dimorphilus gyrociliatus; BUGNE, Bugula neritina; SCHHA, Schistosoma haematobium; SCHSO, Schistocephalus solidus; 9BILA, A. steineri; EUMVA, Eumeta variegata; 9EUPU, Arion vulgaris; LINUN, Lingula unguis; ARAVE, Araneus ventricosus; AMPQE, Amphimedon queenslandica; DANRE, D. rerio. (B) Simplified cladogram showing the phylogeny of REX1 and REX3 genes. (C) Structural overlay of AF models for Rex3 from S. cerevisiae and Q9N5W0 from C. elegans. Domains and termini are labelled.CC BY · PubMed Central

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Metadata

Authors
Daniels, P. W., Kelly, S., Tebbs, I. J., & Mitchell, P.
Affiliations
University of Sheffield (GB)
ORCID
Venue
PLOS One
Publisher
Public Library of Science (PLoS)
Published
2025-06-02
Volume
20
Issue
6
Pages
e0321120
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0321120
PMC
PMC12129344
OpenAlex
W4410950275
Cited by
1
References
5
Citations by year
2026: 1
FWCI
0.30
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, other-oa)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Biotechnology and Biological Sciences Research Council (BB/V00722X/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
Rex1, KIX domain, RNase MRP, tRNA processing, Saccharomyces cerevisiae, protein structure model, protein evolution
MeSH terms
Protein Domains, Amino Acid Sequence, Exoribonucleases, Models, Molecular, Phylogeny, RNA, Transfer, Saccharomyces cerevisiae, Conserved Sequence, Catalytic Domain, Amino Acid Motifs, Saccharomyces cerevisiae Proteins

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