Eukaryotic transcription regulators derive from ancient enzymatic domains
1998; Elsevier BV; Volume: 8; Issue: 4 Linguagem: Inglês
10.1016/s0960-9822(98)70982-0
ISSN1879-0445
Autores Tópico(s)Bacterial Genetics and Biotechnology
ResumoTranscription regulation in eukaryotes comprises two overlapping systems: transcription factors, which are largely responsible for specificity, and chromatin-associated factors, which mediate changes in chromatin conformation, for example, nucleosome unfolding [1Felsenfeld G Chromatin unfolds.Cell. 1996; 86 (96291395): 13-19Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 2Edmondson DG Roth SY Chromatin and transcription.FASEB J. 1996; 10 (96352606): 1173-1182Crossref PubMed Scopus (54) Google Scholar]. The evolutionary history of these proteins is generally unclear. Some are highly conserved among eukaryotes and appear to have evolved early in eukaryotic evolution, whereas others seem to be confined to distinct eukaryotic lineages; most have no obvious orthologs in bacteria or archaea. We show here that three unrelated families of transcriptional regulators, Gal80, TAFII150, and Cdc68/Spt16, derive from ancient enzymatic domains and that their evolution included disruption of enzymatic active sites. Gal80 is a negative regulator of Gal4, which is the transcriptional activator of galactose-regulated genes [3Lohr D Lopez J GAL4/GAL80-dependent nucleosome disruption/deposition on the upstream regions of the yeast GAL1–10 and GAL80 genes.J Biol Chem. 1995; 270 (96070896): 27671-27678Crossref PubMed Scopus (26) Google Scholar, 4Zenke FT Engles R Vollenbroich V Meyer J Hollenberg CP Breunig KD Activation of Gal4p by galactose-dependent interaction of galactokinase and Gal80p.Science. 1996; 272 (96247322): 1662-1665Crossref PubMed Scopus (125) Google Scholar]. Gal80 is conserved in two yeast species, Saccharomyces cerevisiae and Kluyveromyces lactis, but no orthologs are currently detectable in other species. Sequence comparisons indicate that Gal80 is related to a widespread family of oxidoreductases typified by glucose-fructose oxidoreductase (GFOR; Figure 1a). The sequence similarity between Gal80 and GFOR family oxidoreductases is statistically significant, and the dinucleotide-binding Rossmann fold typical of the GFOR structure [[5]Kingston RL Scopes RK Baker EN The structure of glucose-fructose oxidoreductase from Zymomonas mobilis: an osmoprotective periplasmic enzyme containing non-dissociable NADP.Structure. 1996; 4 (97148336): 1413-1428Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar] appears to be conserved in Gal80 (Figure 1a). The catalytic site, however, which in the GFOR superfamily contains the conserved glutamic acid–lysine–proline triad, is disrupted in Gal80 (Figure 1a), suggesting that Gal80 lacks enzymatic activity, though it still may bind a nucleotide and/or a sugar. These affinities of the Gal80 GFOR-related fold may account for the ATP-dependent effect of galactose on Gal4 inhibition [[6]Yano K Fukasawa T Galactose-dependent reversible interaction of Gal3p with Gal80p in the induction pathway of Gal4p-activated genes of Saccharomyces cerevisiae.Proc Natl Acad Sci USA. 1997; 94 (97203127): 1721-1726Crossref PubMed Scopus (87) Google Scholar]. Drosophila TAFII150 is a basal transcription factor conserved in yeast (Tsm1) and other eukaryotes; it is a component of TFIID, which contacts DNA in the vicinity of the transcription start site [[7]Verrijzer CP Chen JL Yokomori K Tjian R Binding of TAFs to core elements directs promoter selectivity by RNA polymerase II.Cell. 1995; 81 (95323967): 1115-1125Abstract Full Text PDF PubMed Scopus (255) Google Scholar] and modulates promoter selectivity and transcription activation [[8]Verrijzer CP Yokomori K Chen JL Tjian R Drosophila TAFII150: similarity to yeast gene TSM-1 and specific binding to core promoter DNA.Science. 1994; 264 (94233377): 933-941Crossref PubMed Scopus (176) Google Scholar]. Database searches revealed significant sequence similarity between TAFII150/Tsm1 and the aminopeptidase N (AMPN) family, which includes enzymes involved in the degradation of a variety of peptides and leukotrienes [[9]Cadel S Foulon T Viron A Balogh A Midol-Monnet S Noel N Cohen P Aminopeptidase B from the rat testis is a bifunctional enzyme structurally related to leukotriene-A4 hydrolase.Proc Natl Acad Sci USA. 1997; 94 (97250473): 2963-2968Crossref PubMed Scopus (67) Google Scholar]. TAFII150 proteins contain the four conserved blocks typical of this family, but lack the two metal-chelating histidines (Figure 1b). The other conserved residues are retained, suggesting that the transcription regulators have the same overall structure as the AMPN family enzymes. Cdc68/Spt16 is a chromatin-associated protein that upregulates transcription and acts antagonistically to the RING finger protein silencer protein San1 [[10]Xu Q Johnston GC Singer RA The Saccharomyces cerevisiae Cdc68 transcription activator is antagonized by San1, a protein implicated in transcriptional silencing.Mol Cell Biol. 1993; 13 (94067116): 7553-7565Crossref PubMed Scopus (34) Google Scholar]. Likely orthologs of Cdc68 are detectable among human and plant expressed sequence tags (ESTs). Sequence comparisons show that Cdc68/Spt16 and its homologs belong to the aminopeptidase P (AMPP) superfamily involved in cleaving proline-containing peptides, creatine hydrolysis, and agropine synthesis [[11]Bazan JF Weaver LH Roderick SL Huber R Matthews BW Sequence and structure comparison suggest that methionine aminopeptidase, prolidase, aminopeptidase P, and creatinase share a common fold.Proc Natl Acad Sci USA. 1994; 91 (94195764): 2473-2477Crossref PubMed Scopus (146) Google Scholar]. As in the case of TAFII150/Tsm1, the aminopeptidase catalytic site, centered around the metal-chelating histidines, is disrupted in Cdc68/Spt16, which is therefore unlikely to possess hydrolase activity (data not shown). Another member of the AMPP superfamily, Cdb1/Pas1, which is highly conserved in eukaryotes, is a nuclear, curved-DNA-binding protein [12Yamada H Mori H Momoi H Nakagawa Y Ueguchi C Mizuno T A fission yeast gene encoding a protein that preferentially associates with curved DNA.Yeast. 1994; 10 (95076708): 883-894Crossref PubMed Scopus (30) Google Scholar, 13Radomski N Jost E Molecular cloning of a murine cDNA encoding a novel protein, p38–2G4, which varies with the cell cycle.Exp Cell Res. 1995; 220 (96032817): 434-445Crossref PubMed Scopus (95) Google Scholar]. Similarly to Cdc68/Spt16, Cdb1/Pas1 lacks two of the three catalytic histidines (data not shown), suggesting a more general involvement of inactive AMPP proteins in chromatin-associated roles. We have shown that three unrelated yeast transcriptional regulators, two of them highly conserved among eukaryotes, have probably evolved from ancient enzymatic domains. In each case, the active site is disrupted, indicating elimination of the enzymatic activity, with retention of the overall structure and probably protein–protein interactions and ligand-binding capacities. The independent recruitment of two aminopeptidases for transcription regulation is of special interest, suggesting that the innate protein-binding properties of proteases make them particularly prone to recruitment for non-enzymatic roles. The only other case of an enzyme recruited as a eukaryotic transcription regulator known to us — preadipocyte factor AEBP1 — also involves a protease, in this case an active carboxypeptidase [[14]He GP Mulse A Li AW Ro HS A eukaryotic transcriptional repressor with carboxypeptidase activity.Nature. 1995; 378 (96061010): 92-96Crossref PubMed Scopus (133) Google Scholar]. Systematic analysis of the sequences and structures of eukaryotic transcription regulators with increasingly sensitive computer methods will show how common it is for them to have evolved from enzymes. L Aravind, Department of Biology, Texas A&M University, College Station, Texas 70843 and National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA. EV Koonin (corresponding author): National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA. e-mail: [email protected]
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