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Activation Functions 1 and 2 of Nuclear Receptors: Molecular Strategies for Transcriptional Activation

Departments of BioSciences (A.W., E.T., A.P.H.W., J.-Å.G.) and Medical Nutrition (J.-Å.G.), Novum, Karolinska Institutet, S-141 57 Huddinge, Sweden; and Section for Natural Sciences (A.P.H.W.), Södertörns Högskola, S-141 89 Huddinge, Sweden

Address all correspondence and requests for reprints to: Anette Wärnmark, Karolinska Institutet, Department of Biosciences at Novum, SE-141 57 Huddinge, Sweden. E-mail: anette.warnmark{at}biosci.ki.se.

	ABSTRACT

TOP ABSTRACT INTRODUCTION STRUCTURE OF AF DOMAINS COACTIVATOR BINDING STRATEGIES FOR AF-1 AND... REFERENCES

 
Nuclear receptors (NRs) comprise a family of ligand inducible transcription factors. To achieve transcriptional activation of target genes, DNA-bound NRs directly recruit general transcription factors (GTFs) to the preinitiation complex or bind intermediary factors, so-called coactivators. These coactivators often constitute subunits of larger multiprotein complexes that act at several functional levels, such as chromatin remodeling, enzymatic modification of histone tails, or modulation of the preinitiation complex via interactions with RNA polymerase II and GTFs. The binding of NR to coactivators is often mediated through one of its activation domains. Many NRs have at least two activation domains, the ligand-independent activation function (AF)-1, which resides in the N-terminal domain, and the ligand-dependent AF-2, which is localized in the C-terminal domain. In this review, we summarize and discuss current knowledge regarding the molecular mechanisms of AF-1- and AF-2-mediated gene activation, focusing on AF-1 and AF-2 conformation and coactivator binding.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION STRUCTURE OF AF DOMAINS COACTIVATOR BINDING STRATEGIES FOR AF-1 AND... REFERENCES

 
NUCLEAR RECEPTORS (NRs) are ligand-inducible transcription factors, and like other transcription factors they contain a distinct DNA binding domain that allows for target gene recognition and activation domains that possess the ability to activate transcription. A large number of activation domains from different eukaryotic transcription factors have been identified, but the molecular mechanisms behind their ability to activate transcription are not well understood. One major reason for the slow progress in this field has been the poor intrinsic propensity for structure formation of these activation domains (1, 2, 3, 4), which has made classical structure-function approaches more difficult. Many NRs have at least two activation domains, the ligand-independent activation function (AF)-1, which generally resides in the N-terminal region, and the ligand-dependent AF-2, which is localized in the C-terminal ligand-binding domain (LBD) (5, 6, 7, 8, 9, 10). Full transcriptional activity of an NR is achieved through synergism between its AFs. Moreover, the transcriptional potential of each activation function is dependent on external determinants such as promoter context, cell type, and posttranslational modifications (e.g. phosphorylation) (11, 12, 13, 14, 15, 16, 17). All AF-1/N-terminal regions of NRs studied so far belong to the large category of intrinsically disordered activation domains. This is in contrast to the AF-2 domain, localized within the LBD, which is highly structured. Instead of being built up from a stretch of amino acids with poor intrinsic structure, the AF-2 domain consists of a surface created by different structural elements in the LBD.

Once bound to DNA, NRs act by recruiting general transcription factors or intermediary factors (coactivators), which are often subunits in protein complexes that stabilize the preinitiation complex containing the RNA polymerase or remodel chromatin. The basis for these recruitments is the formation of protein-protein interactions. In this review, we will summarize and discuss current knowledge regarding the molecular mechanisms of AF-1- and AF-2-mediated gene activation. The apparent differences between AF-1 and AF-2 in conformation and coactivator binding suggest that the two activation functions have evolved different strategies to activate target genes, and here we propose molecular models for coactivator recruitment by AF-1 and AF-2.

	STRUCTURE OF AF DOMAINS

TOP ABSTRACT INTRODUCTION STRUCTURE OF AF DOMAINS COACTIVATOR BINDING STRATEGIES FOR AF-1 AND... REFERENCES

 
It has so far not been possible to determine the tertiary structure of intact receptors. Full-length NRs are extremely difficult to express and purify and in the few reported cases where this has been achieved the amount of protein has been too low or crystals have not been formed. Thus, conformational studies of NRs have so far involved smaller parts of the receptors, but, nevertheless, very valuable structural information has been obtained. The many crystal structures of the LBDs of different NRs have been of major importance for the rapid progress toward a fuller understanding of the molecular events in AF-2-mediated transcriptional activation. In contrast, little information is available on the conformation of the AF-1 regions, and only a few AF-1 regions have been studied in detail.

AF-1 Domains Have Poor Propensity for Structure Formation
The N-terminal region, which contains AF-1, is the least conserved region among NRs, both in size (N-terminal domains of the vitamin D receptor and the mineralocorticoid receptor are 23 and 602 amino acid residues long, respectively) and sequence (18, 19). Consequently, the activation capacity of AF-1 domains has been shown to vary considerably between different NRs. In addition, many receptor isoforms that differ exclusively in their N-terminal amino acid sequences are generated through alternative splicing and/or alternative promoter usage (20, 21, 22, 23, 24, 25).

Studies applying nuclear magnetic resonance and circular dichroism spectroscopy have shown that the AF-1 region (1) of the glucocorticoid receptor (GR) and the N-terminal regions of the estrogen receptors, estrogen receptor (ER) and ERß, are disordered in aqueous solution (26, 27). Limited proteolysis experiments with the progesterone receptor N terminus have also shown a lack of well-folded structure for this isolated region (28, 29). There is, of course, the possibility that these domains, which are poorly structured in isolation, may be stabilized in the context of the intact receptor. Accordingly, the N-terminal region of progesterone receptor was demonstrated to be more structured when expressed together with its DNA-binding domain (DBD), suggesting intramolecular interactions or allosteric effects in the protein (29, 30). Similar results have also been obtained for the N-terminal domain of GR (31). However, the reported changes were small and there was no evidence for any globular structure formation. In addition, early observations showed that the N terminus of the intact GR is highly sensitive to proteolysis, consistent with the existence of a poorly structured AF-1 domain even in the context of the intact receptor protein (32).

Formation of -Helices and Hydrophobic Surfaces in AF-1 Domains
The GR and hepatocyte nuclear factor 4 (HNF-4) AF-1 domains have a high degree of acidic amino acid content and resemble the activation domains of other viral and cellular transcription factors, such as VP16 (1, 2), nuclear factor-ß p65 (3), and p53 (4), which are also acidic and have been shown to have a disordered structure in solution. In addition, AF-1 domains of GR and ER can activate transcription in yeast cells when bound to their cognate DNA elements (33, 34, 35). Thus, the AF-1 domains of at least some NRs can accomplish gene activation through mechanisms that have been conserved during evolution and which are shared with several other transcription factors.

Mutational analyses of the AF-1 of GR and HNF-4 have shown the importance of hydrophobic amino acids for transcriptional activation, whereas mutation of individual acidic amino acids did not have a major impact (36, 37, 38). Furthermore, in the presence of trifluoroethanol, which is a strong -helix stabilizing agent, the AF-1 region of GR shows considerable -helical characteristics as measured by circular dichroism and nuclear magnetic resonance spectroscopy (26). Mutants with proline substitution mutations within the putative -helical regions reduce the transactivation activity of AF-1 and also the ability of AF-1 to form -helices in trifluoroethanol, suggesting that -helix formation is an important step in AF-1-mediated gene activation (39). When the amino acid sequences of the -helical regions of the GR AF-1 are plotted on the surface of an -helix, the hydrophobic residues form clusters and, interestingly, some mutations that expand the hydrophobic patch result in even higher activity than that of wild type (37), suggesting an important role for these surfaces in inter- and/or intraprotein interactions. Taken together, these results suggest that the AF-1 domain may consist of modules with a propensity for -helical conformation. In line with this notion, artificial constructs containing an abnormal order or composition of these modules retain activity, suggesting that the modules may have at least partially redundant functions (40). In summary, the current limited structure-function data suggest that poor intrinsic structure, secondary structure formation (-helix) and/or formation of hydrophobic surfaces of AF-1 regions are important for AF-1 activated transcription.

The AF-2 Domains of NRs Are Structurally Conserved
The AF-2 is part of the ligand-binding domain (LBD, 250 amino acids), and the conformation of the LBD has been shown to be of crucial importance for AF-2 function. The AF-2 region was initially identified in the mouse ER where deletion analysis demonstrated a large segment of the LBD to be important for ligand-dependent activation (41). Mutation and deletion studies of several LBDs revealed a conserved segment in the very C terminus of the LBDs that was shown to be essential for the ligand-dependent activation of transcription (9, 10, 42, 43). This conserved segment was predicted to be an amphipathic helix, which was later verified in the many LBD crystal structures that have subsequently been solved. Since 1995, when the first NR LBD structures were solved, our knowledge about structure and function of the LBD has increased extensively. The three-dimensional structures of apo-retinoid X receptor (44), and holo-RAR (45) as well as holo-TR (46) showed that the overall structures of the different receptors are similar, revealing a canonical fold for the LBD. Eleven to 12 helices are arranged together in an antiparallel, three-layered sandwich with two to four ß-strands included (47) and in all holo-structures, the cognate ligand binds to a hydrophobic cavity buried within the core of the LBD (48). The holo-structures are more compact than the apo-structures, demonstrating that binding of ligand induces a conformational rearrangement in the domain. Moreover, just recently the crystal structure was solved for the Nurr1 receptor (49), which belongs to the orphan receptor subfamily of NRs for which no ligands are currently known. The structure revealed a fold that resembles that of the known agonist-bound LBDs, but lacks the ligand-binding pocket as result of the tight packing of bulky hydrophobic residues. This suggests that Nurr1 may be a true orphan receptor to which no ligands exist.

Position of the C-Terminal Helix 12—A Critical Determinant of AF-2 Function
Very important for the understanding of AF-2 function was the observation that in the unliganded structures of retinoid X receptor (44) and peroxisomal proliferator-activated receptor (50), the most C-terminal helix, helix 12, which contains the conserved segment, projects away from the core structure, whereas, in the liganded receptor structures, helix 12 is folded up against the core, creating a lid over the ligand-binding pocket. Since then, many NR-ligand crystal structures demonstrating different positions of helix 12 have been solved and thorough descriptions of these structures can be found elsewhere (48, 51, 52, 53, 54, 55). The structural data, together with transcriptional activation data, imply that the positioning of helix 12 is crucial for receptor activation. However, it has been suggested that activation of AF-2 is determined by the equilibrium of different helix 12 conformations and that a ligand does not usually induce one static conformation, but rather changes the equilibrium toward more active conformations in the case of agonists and inactive conformations in the case of antagonists (52). Finally, it is important to remember that the conserved helix 12 alone is not sufficient to function as a transactivation domain; instead it constitutes, in its active mode, part of an activation surface together with additional parts of the LBD, which together define the AF-2 domain.

	COACTIVATOR BINDING

TOP ABSTRACT INTRODUCTION STRUCTURE OF AF DOMAINS COACTIVATOR BINDING STRATEGIES FOR AF-1 AND... REFERENCES

 
To achieve transcriptional activation of target genes, DNA-bound NRs were originally believed to directly recruit general transcription factors (GTFs) to the preinitiation complex. Subsequent research revealed, however, that most NR regulated transcription events also require intermediary factors. These proteins, so-called coregulators, often constitute subunits of larger multiprotein complexes that act at several functional levels, such as chromatin remodeling, enzymatic modification of histone tails, or modulation of the preinitiation complex via interactions with RNA polymerase II and GTFs. Most NR coregulators can be subdivided into coactivators and corepressors, respectively, depending on whether they mediate transcriptional activation or repression. Potential NR coactivators constitute a structurally diverse group of proteins that have been identified using biochemical and expression cloning approaches. Many of these proteins have been shown to potentiate NR-mediated transactivation in transient transfection assays or in vitro transcription studies, supporting their role as NR coactivators. Two distinct groups of coactivators have emerged: ligand-dependent coactivators that bind to the AF-2 in the LBD, and coactivators that are associated with the N-terminal AF-1 region. In addition, some coactivators can apparently bind to both the AF-1 and AF-2 regions of a receptor (56, 57). There are also proteins suggested to act as coactivators that bind to other regions of the receptors.

Repression of transcription is also a very important event in gene regulation and may be achieved through several different mechanisms involving corepressors. Furthermore, it has become clear that coactivation or corepression is not necessarily an intrinsic feature of a given coregulator but can depend on the target gene and cell-type specific context, i.e. some coregulators can function either as a coactivator or a corepressor in a context-dependent manner (58, 59). It is evident that NR-dependent gene regulation is very complex and requires the concerted action of a large number of coregulatory proteins. The coregulator field has expanded rapidly and the number of known coregulators has constantly increased. A complete description of different coregulators lies outside the scope of this paper, but appropriate reviews have been published elsewhere (56, 57, 60).

Complex Formation Induces Structure in the AF-1 Domain
Several different coactivators have been shown to bind to the AF-1 function of NRs, but the structural basis for these interactions is not well understood. For example, the TATA box-binding protein (TBP), the Alteration/deficiency of activation 2 protein (Ada2p), the cAMP response element binding protein-binding protein and the vitamin D receptor-interacting protein 150 have all been shown to be direct targets for the AF-1 region of GR (61, 62, 63, 64), but these coactivators contain no sequence or known structural homologies.

As already discussed, all isolated AF-1 or N-terminal domains studied have been shown to be structurally disordered (26, 27, 29, 30, 65), but it has been suggested that secondary structure formation is an important step in AF-1-mediated activation (26, 27). Consistent with this, complex formation between isolated ER N-terminal domain protein and TBP is accompanied by a change in conformation (27). The most likely explanation for this effect is that the highly structured TBP stabilizes or induces a folded form of the N-terminal domain of the receptor. In line with this notion, the transactivation regions of several other transcription factors, such as VP16, cAMP response element binding protein, p53, and c-Myc, have been shown to undergo a transition to a folded state upon interaction with interaction motifs of coactivators (4, 66, 67, 68, 69).

AF-1-Coactivator Binding Characteristics
In studies of TBP-binding to the ER N terminus, using surface plasmon resonance real-time measurements, the binding curve characteristics suggested an initial rapid association phase of the unstructured ER N terminus to the TBP surface, followed by a slow binding phase during which conformational adaptation might take place (27). Furthermore, the dissociation phase of the binding curve suggested a rapid dissociation for ER molecules that did not undergo proper folding and a slower dissociation of molecules that did fold successfully upon interaction with the TBP surface. Such a two-step binding mechanism supports an induced fit model for AF-1-coactivator interaction in which the change in protein conformation occurs on the surface of the binding partner.

An alternative biphasic interaction model is the collection model where the population of unstructured activator molecules could be seen as a collection of many different conformations. In this collection, some molecules are assumed to have the proper fold for target binding and binding of these properly folded activators to their target protein leads to a change in collection equilibrium toward the active conformations, which then drives the formation of activator-target complexes.

However, the induced fit model, in which the change in protein conformation occurs on the surface of the binding partner, is supported by a general model for activator-target interactions first developed to describe interactions between the c-Myc activation domain and TBP (70). c-Myc rapidly forms an unstable complex, mainly via electrostatic interactions that subsequently converts to a more stable form that is dependent on hydrophobic interactions. This strongly suggests a template-directed folding mechanism for the interaction in which the final structure of the activation domain is influenced by, in this case, the surface of TBP (Fig. 1). This interaction model helps to explain mutagenesis data for several activators, including GR and HNF-4 (36, 37, 38), showing the importance of both general acidity and key hydrophobic amino acid residues for activity. The acidic residues would be important for the first phase of the interaction, whereas the hydrophobic residues would play a critical role in the subsequent template-directed folding step. Hermann et al. (70) suggest that at least under some conditions, such as high activator expression levels and target genes with multiple activator binding sites, it might be possible to obtain activation via first-phase ionic interactions alone. This could explain early observations that peptides from proteins unrelated to transcription factors could sometimes mediate gene activation (71, 72). The template-mediated folding mechanism of interaction can clarify how activators make specific interactions with a large range of structurally diverse target proteins, since the activation domain would be able to adopt distinct optimized conformations when bound to different interaction partners. It has also been suggested that a binding mechanism in which the activation domain does not fold into a specific structure until it encounters a coregulator can be kinetically and thermodynamically advantageous (73, 74).

View larger version (15K): [in this window] [in a new window]   Fig. 1. Binding Model for Unfolded Activation Domain Toward Its Coactivator The activation domain rapidly binds to the coactivator, via weak electrostatic interactions. Subsequently, the complex slowly converts to a more stable form and the activation domain folds into a defined structure (70 ).

Unliganded (inactive) steroid receptors are known to be sequestered in a multiprotein complex containing various molecular chaperones (76). In addition, molecular chaperones are suggested to be important in post-DNA binding events of NR-mediated gene expression (77, 78, 79). No chaperone that directly targets the AF-1 has been identified, and if chaperones would participate in shaping a structure in the AF-1 domain, AF-1 coactivator binding could still work according to the proposed induced fit model as this model does not require unfolded proteins. An equilibrium between folded AF-1 and a small pool of transiently unfolded AF-1 would be sufficient.

AF-2 Coactivator Binding
As in the case of AF-1, AF-2 is the target for several coactivators, but in contrast, almost all coactivators that have been identified as AF-2 interacting proteins contain conserved leucine-rich motifs with the consensus sequence LXXLL (L, leucine; X, any amino acid) and display ligand-dependent interaction (80). The LXXLL motif (NR box) has been demonstrated to be necessary and sufficient for the interaction between the receptor and the coactivator (80, 81), and multiple motifs usually reside within a distinct NR interacting domain.

The structural rearrangement of the LBD upon cognate ligand binding generates the surface to which the LXXLL interaction domain of coactivators binds. Several crystal structures of ligand-bound LBD/NR-box peptide complex have revealed the structural basis for AF-2 domain/coactivator interaction (50, 82, 83). In all structures, the LXXLL motif forms an -helix and is bound to a hydrophobic groove on the LBD. The coactivator peptide is held in place through hydrophobic interactions via its leucines and the hydrophobic groove of the receptor. Furthermore, lysine at the C terminus of helix 3 and a glutamate in helix 12 are hydrogen bonded to peptide bonds in the LXXLL peptide forming a charge clamp that stabilizes the receptor/peptide interaction. In conclusion, the structural basis for AF-2 ligand-dependent activation is stabilization of helix 12 over the ligand-binding pocket upon ligand binding, creating the activation surface/AF-2 domain, which allows the docking of the LXXLL coactivator and the formation of a charge clamp that stabilizes the NR-coactivator interaction.

Alternative Coactivator Recruitment
The androgen receptor displays in many respects a unique mechanism of transcriptional activation compared with other described receptors. Most of its transcriptional activity is mediated through its N-terminal AF-1 domain (84), which contains homopolymer stretches of glutamine and glycine amino acids (85). Similar to what has been shown for other NRs, the AF-1 domain of AR possesses limited secondary structure in aqueous solution and has been demonstrated to acquire a more folded conformation upon binding to a coregulator protein (86). Most interestingly, the AF-2 of AR has been shown to have a reduced capacity to recruit LXXLL containing coactivators compared with other steroid receptors (87). Instead, the AF-2 domain of AR is suggested to act primarily as an interaction platform for the N-terminal region enabling recruitment of coactivators to AR in an LXXLL motif-independent manner (88).

Two LXXLL-like motifs, FXXLF and WXXLF, in the AF-1 domain of AR have been found to be responsible for the interaction with the C-terminal region of AR (89). The interaction between the N terminus and the C terminus is ligand dependent and stabilizes receptor/ligand interaction (87, 90). Furthermore, the intraprotein interaction has been shown to be required for AR-mediated transactivation in vivo (91, 92, 93, 94).

	STRATEGIES FOR AF-1 AND AF-2 TRANSCRIPTIONAL ACTIVATION

TOP ABSTRACT INTRODUCTION STRUCTURE OF AF DOMAINS COACTIVATOR BINDING STRATEGIES FOR AF-1 AND... REFERENCES

 
Opposite Structural Features
The available information from structure-function studies suggests that the two domains, AF-1 and AF-2, use two different strategies to achieve transcriptional activation (Fig. 2). The AF-1 domains of NRs are unfolded and not conserved in size or sequence, whereas the AF-2 domains form defined globular structures and are conserved. The ligand-binding event modulates AF-2 activation by determining the coactivator binding capacity. Consistent with the degree of conservation of the AF domains, the coactivators of AF-2 contain highly conserved interaction motifs, whereas the coactivators of AF-1 do not share any common motifs. An unstructured AF-1 domain could be a prerequisite to allow for interactions with different nonconserved coactivator interaction domains. However, it is important to note that the AF-1 coactivator interaction is selective and the structure/s induced in AF-1 upon coactivator binding is/are believed to be specific. In other words, AF-1 domains do not interact indiscriminately with all proteins encountered and the different AF-1 domains of NRs interact with different sets of proteins. Although the binding domains of AF-1 coactivators obviously lack sequence conservation, it cannot be excluded that common structures or folds exist.

View larger version (23K): [in this window] [in a new window]   Fig. 2. Molecular Strategies for Transcriptional Activation A, Interaction of disordered AF-1 domain with different unrelated coactivators leads to complex formations in which the AF-1 domain folds into template (coactivator) directed conformations. B, Induced conformation in LXXLL containing coactivators upon complex formation with the AF-2 domain.

Unifying Biphasic Coactivator Binding Characteristics
In binding studies of the two ER subtypes with either different LXXLL peptides or intact NR-interaction domains of the two coactivators transcriptional intermediary factor 2 and thyroid hormone receptor-associated protein 220 (56, 57), the biphasic conformational change model best described the binding curves obtained (95, 96, 97). Thus, the induced fit model in which one of the proteins undergoes a transition to a folded state upon interaction with its binding partner could also account for the AF-2/coactivator interaction. Hypothetically, recognition of AF-2 could occur in an unstructured environment via charged residues adjacent to the leucine residues of the LXXLL motif. This could lead to subsequent formation of an interaction-induced -helical structure within the coactivator, and finally to high affinity binding of the invariant leucine core to the AF-2 surface. This model is further supported by a recent study showing that besides the conserved charge clamp residues additional charged residues in the LBD of the receptor and charged residues flanking the LXXLL motifs in the coactivator are important for AF-2 coactivator recruitment (98). In conclusion, a unifying model for coactivator binding to AF-1 and AF-2 can be proposed in which initial contact via electrostatic interactions, binding partner-induced -helix formation and consequent establishment of hydrophobic interaction surfaces are critical for stable complex formation and subsequent gene activation by both activation functions.

	FOOTNOTES

 
This work was supported by grants from the Swedish Science Council and KaroBio AB.

Abbreviations: AF, Activation function; DBD, DNA-binding domain; ER, estrogen receptor; GR, glucocorticoid receptor; GTF, general transcription factors; HNF-4, hepatocyte nuclear factor 4; L, leucine; LBD, ligand-binding domain; NR, nuclear receptor; TBP, TATA box-binding protein; X, any amino acid.

Received for publication November 19, 2002. Accepted for publication July 25, 2003.

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TOP ABSTRACT INTRODUCTION STRUCTURE OF AF DOMAINS COACTIVATOR BINDING STRATEGIES FOR AF-1 AND... REFERENCES

 

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