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Identification of the C-Terminal Activator Domain in Yeast Heat Shock Factor: Independent Control of Transient and Sustained Transcriptional Activity

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Identification of the C-Terminal Activator Domain in Yeast Heat Shock Factor: Independent Control of Transient and Sustained Transcriptional Activity The EMBO Journal vol.12 no.13 pp.5007-5018, 1993 Identification of the C-terminal activator domain in yeast heat shock factor: independent control of transient and sustained transcriptional activity Yuqing Chen1, Nickolai A.Barlev2,3, Introduction Ole Westergaard and Bent K.Jakobsen4 In response to hyperthermia, and certain other forms of Department of Molecular Biology, University of Aarhus, C.F.Mollers stress, cells transiently increase transcription from a small Alle, Building 130, DK-8000 Aarhus C, Denmark group of genes that encode a characteristic set of proteins, lPresent address: Department of Zoology, University of Western the heat shock proteins. The heat shock proteins exercise Ontario, London, Canada protective functions in the cell during stress, for instance 2Present address: Laboratory of Structural Genome Organization, Institute of Cytology, Tihkoretsky Avenue 4, 194064 St Petersburg, by renaturing or solubilizing denatured proteins (for reviews Russia see Lindquist, 1986; Pelham, 1986; Bienz and Pelham, 3Present address: Wistar Institute, Pennsylvania University, 1987). 3601 Spruce Street, Philadelphia, PA 19104-4268, USA Heat shock promoters contain a universal sequence 4Present address: Institute of Molecular Medicine, University of element that is necessary and sufficient for their Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK transcriptional activation (the heat shock element, HSE). This Communicated by H.R.B.Pelham was originally identified as a 14 bp sequence by deletion analysis of the Drosophila hsp7O promoter (Bienz and In yeast, heat shock factor (HSF) is a trimer that binds Pelham, 1982; Pelham, 1982; Pelham and Bienz, 1982). DNA constitutively but only supports high levels of Careful examination of the HSE has demonstrated that it can transcription upon heat shock. The C-terminal regions be considered as tandem arrays of inverted 5 bp units with of HSF from Saccharomyces cerevisiae and Kluyveromyces the consensus sequence -GAA- (Amin et al., 1988; Xiao and lactis are unconserved yet both contain strong Lis, 1988). Natural promoters contain various numbers of transactivators which are correctly regulated when the 5 bp units in several different arrays (Amin et al., 1988; substituted for each other. We have performed high Xiao and Lis, 1989). HSEs are recognition sites for a nuclear resolution mapping of these activator domains which protein, the heat shock factor, HSF (Wu, 1985); the 5 bp shows that in K.lacts HSF (KIHSF) activity can be located sequence is the unit of interaction with HSF but stable to a confined short domain, while in S.cerevisiae HSF binding requires at least two inverted 5 bp motifs (Perisic (ScHSF) two separate regions are required for full et al., 1989; Xiao and Lis, 1989; Lis et al., 1990; Xiao activity. Alignment of the activator domains reveals etal., 1991). similarity, as both overlap potential leucine zipper motifs In Drosophila melanogaster and mammalian cells, HSF (zipper C) with a distribution of hydrophobic residues binds DNA only weakly under normal conditions but its sinilar to two highly conserved N-terminal domains affinity is increased markedly by heat shock (Kingston et al., which mediate HSF trimerization (zippers A and B). In 1987; Sorger et al., 1987; Zimarino and Wu, 1987). In these higher eukaryotes a C-terminal leucine zipper is required cell types the crucial modification to HSF may trigger a to maintain HSF in a monomeric and non DNA-binding conformational change that allows oligomerization and state under normal conditions and we therefore address thereby increases DNA affinity (Larson et al., 1988; the regulatory roles of the three leucine zipper motifs in Zimarino and Wu, 1990; Rabindran et al., 1993; Sarge KIHSF. Whilst the longest and most N-terminal of the et al., 1993). In the yeasts S. cerevisiae and K. lactis, by trimer region zippers, A, is dispensable for regulation, contrast, HSF binds DNA constitutively at all physiological mutation of a single leucine in zipper B makes HSF temperatures (Sorger et al., 1987; Jakobsen and Pelham, constitutively active. In contrast to the situation in higher 1988, 1991). Transcription in yeast must therefore be eukaryotes disruption of zipper C has no observable regulated through modification of prebound HSF. regulatory effect and therefore, although an intra- HSF genes have been isolated from a number of organisms molecular contact between zippers B and C cannot be including S. cerevisiae (Sorger and Pelham, 1988; ruled out, such contact is not required for restraining Wiederrecht et al., 1988), K. lactis (Jakobsen and Pelham, the C-terminal activator domain. We furthermore fimd 1991), Drosophila (Clos et al., 1990), human (Rabindran that deletions which abolish activator potential of the et al., 1991), mouse (Sarge et al., 1991) and tomato (Scharf C-terminus render the host strain temperature sensitive. et al., 1990). In yeast, HSF is a single copy essential gene However, deletion of a double proline-glycine motif in whilst in man and mouse two alleles have been identified. the activator, whilst leaving HSF unable to respond to All HSFs contain two conserved domains: a basic DNA heat shock, does not cause temperature sensitivity. This binding surface (Nieto-Sotelo et al., 1990) and a helical result demonstrates that independent mechanisms control domain which has been shown in S. cerevisiae and the transient and sustained activities of HSF. Drosophila HSF to mediate trimerization (Perisic et al., Key words: activators/heat shock proteins/leucine zipper/ 1989; Sorger and Nelson, 1989; Clos et al., 1990; Rabindran transcription regulation/yeast et al., 1993). In addition, the yeast genes share two short homologous stretches, termed CE1 and CE2. © Oxford University Press 5007 Y.Chen et al. Mutational analyses of the yeast genes have illustrated the formation by forming heat shock sensitive interactions with fundamental arrangement of these proteins. Both contain the coiled-coil structures in the N-terminal part of the protein C-termini with high transactivator potentials (the C-terminal (Nakai and Morimoto, 1993; Rabindran et al., 1993). activator, CTA) which are constitutive when assayed by Although the yeast HSFs form trimeric complexes at all fusion to the heterologous DNA-binding proteins lexA or temperatures, the possible association of the activator domain API (Nieto-Sotelo et al., 1990; Sorger, 1990; Jakobsen and with a conserved interaction surface nevertheless suggests Pelham, 1991). Deletion of the CTA reduces the activity that the leucine zippers may form similar structures in all of HSF 3- to 4-fold and causes temperature sensitivity for eukaryotic HSFs. We therefore address the importance of the host strain. The truncated HSF must contain another the three leucine zipper domains for yeast HSF regulation. activity domain though it is likely that this is much less potent Of the N-terminal leucine zippers, the longest, A, is than the C-terminal activator (CTA) since it has not been dispensable for normal activity regulation while the whole possible to identify such a domain by fusion of N-terminal of zipper B is required to restrain both the N- and C-terminal fragments of HSF to lex (Sorger, 1990; Jakobsen and activators in HSF. Thus, control of HSF activity does not Pelham, 1991). require trimerizationper se but is a specific function ofzipper Mutation or deletion of three regions of HSF results in B. In the C-terminus, the activator domain is essential for deregulation. Surprisingly, deletion of the trimer region is normal HSF activity and for the host strain's ability to grow not lethal but leads to HSF having high constitutive activity at high temperature. Regulation is not affected by the (Nieto-Sotelo et al., 1990; Jakobsen and Pelham, 1991). integrity of zipper C and therefore a zipper B -C contact Deregulation, with HSF having somewhat lower activity, is not required for repression of HSF activity in yeast. One is also the result of deletion or mutation of CE2 in the yeast mutation in the activator region, however, locks HSF in a HSFs. It has been suggested that this element is involved virtually inactive state, but despite being unable to respond in an intramolecular contact with another conserved domain to heat shock the host strain grows at all normal and that this structure is required for restraining the CTA temperatures. This result demonstrates that the C-terminal (Jakobsen and Pelham, 1991; for review see Sorger, 1991). activator domain is regulated in two independent ways to Recent results indicate that this element influences the supply heat shock induced and sustained activities. sustained activity mediated by yeast HSF rather than being Furthermore this observation shows that structure in the C- involved in the heat shock response (A.kHoj and B.K.Jakobsen, terminus can influence unmasking of both the C- and N- submitted). Finally, a mutation in the DNA-binding domain terminal activators in HSF which could indicate that close causes constitutive activity, albeit in a fusion protein where physical contact exists between N-terminal and C-terminal the CTA had been exchanged with a heterologous activator domains. We have therefore taken initial steps to look for (Bonner et al., 1992). contact potential between these regions of HSF. In an in vivo From these analyses it is clear that complex intramolecular transcription assay we find that oligomerization can take contacts in HSF are required to restrain activity of the CTA. place between A-B and A-CTA peptides but not between How then is the activator unmasked in response to heat A and A-CTA. Thus ability to form interactions may exist shock? Gel retardation experiments have shown that between zipper B and structures in the C-terminus. HSF-DNA complexes formed with HSF from heat shocked cells migrate more slowly than when formed with HSF from Results unshocked cells (Sorger et al., 1987; Sorger and Pelham, 1988). This difference can be virtually eliminated by treating Mapping of the C-terminal activator in K.lactis HSF HSF with phosphatase.
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