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. 2015 May 4;7(5):1363-79.
doi: 10.1093/gbe/evv068.

Evolution of proteasome regulators in eukaryotes

Philippe Fort  1 , Andrey V Kajava  2 , Fredéric Delsuc  3 , Olivier Coux  1
Affiliations

Evolution of proteasome regulators in eukaryotes

Philippe Fort et al. Genome Biol Evol. .

Abstract

All living organisms require protein degradation to terminate biological processes and remove damaged proteins. One such machine is the 20S proteasome, a specialized barrel-shaped and compartmentalized multicatalytic protease. The activity of the 20S proteasome generally requires the binding of regulators/proteasome activators (PAs), which control the entrance of substrates. These include the PA700 (19S complex), which assembles with the 20S and forms the 26S proteasome and allows the efficient degradation of proteins usually labeled by ubiquitin tags, PA200 and PA28, which are involved in proteolysis through ubiquitin-independent mechanisms and PI31, which was initially identified as a 20S inhibitor in vitro. Unlike 20S proteasome, shown to be present in all Eukaryotes and Archaea, the evolutionary history of PAs remained fragmentary. Here, we made a comprehensive survey and phylogenetic analyses of the four types of regulators in 17 clades covering most of the eukaryotic supergroups. We found remarkable conservation of each PA700 subunit in all eukaryotes, indicating that the current complex PA700 structure was already set up in the last eukaryotic common ancestor (LECA). Also present in LECA, PA200, PA28, and PI31 showed a more contrasted evolutionary picture, because many lineages have subsequently lost one or two of them. The paramount conservation of PA700 composition in all eukaryotes and the dynamic evolution of PA200, PA28, and PI31 are discussed in the light of current knowledge on their physiological roles.

Keywords: PA200; PA28; PA700; PI31; evolution; proteasome.

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Figures

F<sc>ig</sc>. 1.—
Fig. 1.—
High conservation of PA700 subunits in the eukaryote supergroups. (A) Synopsis of PA700 subunits distribution in major supergroups. Sequences were identified by reciprocal Blast searches. Black squares: E-values lower than e−80, gray squares: E-values between e−8 and e−80. Taxonomy is indicated on the left and the corresponding species on the right. (B) Phylogenetic tree of the six AAA+ ATPases subunits. The ATPase domains were aligned and trees were produced by PhyML and MrBayes (see Materials and Methods). The two ATPase domains of Cdc48 were used as outgroups. Only PPs and bootstrap proportions of relevant nodes are indicated.
F<sc>ig</sc>. 2.—
Fig. 2.—
Archaeal orthologs of PSMC and PSMD7/PSMD14. (A) Similarity of archaeal proteins with PA700 subunits. Full-length sequences of eukaryotic PA700 subunits were used as queries against archaeal data. Indicated are the accession numbers, the E-values and the taxonomic status of the best hits. Only PSMCs and PSMD14 produced significant scores. (B) Archaeal orthologs of PSMCs. Trees were produced from eukaryotic and archaeal ATPase domains MSA by PhyML and MrBayes (see Materials and Methods). The two ATPase domains of Cdc48 (_N and _C) and Katanin were used as subfamily outgroups (Iyer et al. 2004). (C) Archaeal orthologs of PSMD7/PSMD14 (arrow). Archaea JAMM groups were defined by Hepowit et al. (2012). Trees were produced from eukaryotic and archaeal MPN domains MSA by PhyML and MrBayes (see Materials and Methods). Filled circles figure nodes critical for orthology. Adjacent numbers indicate PPs and bootstrap proportions.
F<sc>ig</sc>. 3.—
Fig. 3.—
PI31/PSMF1 distribution and losses in eukaryotic supergroups. (A) Synopsis of PI31 distribution in major supergroups. Sequences were identified by reciprocal Blast searches. Black squares: E-values lower than e−10, gray squares: E-values between e−1 and e−10. ⊠: no homologous sequences found. Taxonomy is indicated on the left and the corresponding species on the right. Names of species missing PI31 are grayed. (B) PI31 and its interactor Fbxo7 share the FP (Fbxo7 and PI31) domain and a proline-rich domain (upper panel). Fbxo7 also includes an ubiquitin-like domain and an F-box domain. Multiple protein sequence alignment of the proline-rich domain show differences between PI31 and Fbxo7, in particular in the central motif. (C) Phylogenetic tree of PI31 and Fbxo7. PI31 and Fbxo7 sequences were aligned and trees were produced by PhyML and MrBayes (see Materials and Methods). Only PPs and bootstrap proportions of relevant nodes are indicated.
F<sc>ig</sc>. 4.—
Fig. 4.—
PA200 distribution and losses in eukaryotic supergroups. (A). Synopsis of PA200 distribution in major supergroups. Sequences were identified by reciprocal Blast searches. Black squares: E-values lower than e−80, gray squares: E-values between e−8 and e−80. ⊠: homologous sequences not found. Taxonomy is indicated on the left and the corresponding species on the right. Names of species missing PA200 are grayed. (B) Crystal structure of proteasome activator Blm10/PA200 from Saccharomyces cerevisiae (S. cer) (Sadre-Bazzaz et al. 2010) when viewed from the top of the complex with the 20S proteasome (which is omitted for the sake of the clearness). The structure represents a long curved α-solenoid folded on itself. The Blm10/PA200 crystal structure lacks two unstructured regions that link the N-terminal (green), the first α-helical (blue) and the second α-helical one (yellow), ended by the conserved C-terminal Pfam PF11919 domain (magenta). (C) Schematic representation of Blm10/PA200 proteins from different organisms. The upper S. cer protein has the known 3D structure while the others were deduced based on the sequence similarities with the S.cer protein. Rectangles denote α-solenoid structures with HEAT repeats. The color code is the same as on panel B. Black lines connecting the rectangles show regions that were not resolved by the X-ray crystallography. Large insertions of more than 40 residues into the core of the α-solenoids are shown below the rectangular boxes. The insertions that are observed in the 3D structure are colored, while ones that are predicted based on the sequence alignment are in black. The predicted insertions may have structures as shown on panel (D). S. man, Schisostoma mansoni (Platyhelminthes); D. dis, Dictyostelium discoideum (Amoebozoa); E. his, Entamoeba histolytica (Amoebozoa); N. gru, Naegleria gruberi (Heterolobosea); T. vag, Trichomonas vaginalis (Parabasalia); A. tha, Arabidopsis thaliana (Viridiplantae); P. fal, Plasmodium falciparum (Alveolates); G.the, Guillardia theta (Cryptophyta). (D) An example of a large insertion (gray color) into the HEAT repeat unit (1) in comparison with a typical HEAT repeat unit (2). (E) Absence of PA200 in Brachycera insects. Alignment of PA200 orthologs showed that the C-terminus is highly conserved among arthropods and if present, should have been detected in Brachycera.
F<sc>ig</sc>. 5.—
Fig. 5.—
PA28 distribution and losses in eukaryote subgroups. (A) Synopsis of PA28 distribution in major supergroups. Sequences were identified by reciprocal Blast searches. Black squares: E-values lower than e−80. ⊠: homologous sequences not found. Taxonomy is indicated on the left and the corresponding species on the right. Names of species missing PA200 are grayed. The putative ortholog of the Trypanosoma PA26 is indicated as PA26-like. (B) Sequence alignment of PA28 in Opisthokonts, showing the high conservation of the150 C-terminal amino acids. (C) Phylogenetic relationships of Excavate PA26 relative to PA28 from other supergroups. MrBayes and ML trees were generated from PA28 and PA26 C-terminal sequences MSA. Only PP values above 0.7 are indicated.
F<sc>ig</sc>. 6.—
Fig. 6.—
Duplications and losses of PA28 copies in chordates. (A) Synopsis of PA28 isoform distribution in chordates. Sequences similar to PSME1 (REGα/PA28α), PSME2 (REGβ/PA28β), and PSME3 (REGγ/PA28γ) were identified by reciprocal Blast searches. Black squares: E-values lower than e−80. ⊠: homologous sequences not found. Taxonomy is indicated on the left. Chordate taxa showing a single isoform are colored in red and the names of the corresponding species are grayed. (B) PSME phylogeny in chordates. MrBayes and PhyML analysis of the MSA shown in supplementary figure S4, Supplementary Material online, produced the same tree topology. PP and bootstrap proportion are shown only for nodes informative for the duplication history. Short branches that link PSME3 orthologs are signaled by arrowheads and long branches that connect PSME3 to its paralogs, by arrows. Species abbreviation corresponds to species listed in (A).
F<sc>ig</sc>. 7.—
Fig. 7.—
Summary of the distribution of 20S proteasome and proteasome regulators subunits across eukaryote supergroups. The purpose of the timeline of eukaryote emergence, adapted from the Time Tree web page (http://www.timetree.org/index.php, last accessed April 28, 2015), is to give a global view of the supergroups and taxa examined here and of the gain and loss events that have built the current repertoire of proteasome regulators. Note that the complexification process or loss of regulators (crosses) cannot be dated precisely.
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References

    1. Abascal F, Zardoya R, Posada D. ProtTest: selection of best-fit models of protein evolution. Bioinformatics. 2005;21:2104–2105. - PubMed
    1. Adl SM, et al. The revised classification of eukaryotes. J Eukaryot Microbiol. 2012;59:429–493. - PMC - PubMed
    1. Al-Shami A, et al. Regulators of the proteasome pathway, Uch37 and Rpn13, play distinct roles in mouse development. PLoS One. 2010;5:e13654. - PMC - PubMed
    1. Bachvaroff TR, Handy SM, Place AR, Delwiche CF. Alveolate phylogeny inferred using concatenated ribosomal proteins. J Eukaryot Microbiol. 2011;58:223–233. - PubMed
    1. Bader M, et al. A conserved F box regulatory complex controls proteasome activity in Drosophila. Cell. 2011;145:371–382. - PMC - PubMed

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