One small step for Mot1; one giant leap for other Swi2/Snf2 enzymes?

Keywords: TATA-binding protein, TBP, Mot1, BTAF1, Swi2, Snf2, ATPase

2.1. ATPase domain structure and DNA interaction

Structural studies have provided key insights into the mechanism of these enzymes. Many crystal structures of SF1 and SF2 ATPase domains have been reported. These display common features in domain organization and a rich variety of conformational states resulting from nucleotide and/or nucleic acid interaction. Although Swi2/Snf2 enzymes are in the SF2 class, SF1 enzymes are arguably the best studied and the principles of SF1 function have informed models of how other translocases and helicases work [64–67]. The SF1 helicase PcrA has been especially influential in defining general principles of structural organization, as well as how the ATP hydrolysis cycle modulates the conformational state [64]. PcrA possesses four domains designated 1A, 1B, 2A and 2B. 1A and 2A are structurally similar to nucleotide binding domains of the E. coli RecA strand exchange enzyme, and thus are referred to as RecA-like domains [66, 68, 69]. In fact, all reported ATPase structures reveal a similar organization in which the 1A and 2A domains are structurally conserved and RecA-like [57, 70, 71]. The nucleotide binding site is defined by the cleft between the 1A and 2A domains [67, 72]. Nucleic acid substrates bind across the cleft, explaining how the ATP hydrolysis cycle converts rigid body reorientations of the RecA domains to movement of the ATPase along DNA or RNA. The 1B and 2B domains are thought to confer functional specificity, for example, by coupling ATP hydrolysis to structural rearrangements of the nucleic acid substrate [67, 73]. Accessory domains that flank the ATPase core may also be involved in enzyme-specific interactions with other subunits or factors [57, 74–79]. In this way, the fundamental biochemical activity of nucleic acid translocation has been exploited to catalyze a great variety of reactions. This general picture of SF1 helicase structure and function is consistent with SF2 helicase structure and function as well. Among the SF2 helicases, NS3 is probably the best understood on a structural level [64, 80, 81]. Again, the picture that emerges is of an enzyme that uses ATP binding and hydrolysis to interconvert conformational states in tandem RecA folds to propel the motor along a nucleic acid substrate [80].

The architecture of Swi2/Snf2 ATPase domains is similar to the structural organization of SF1 and SF2 helicase motor domains. The first Swi2/Snf2 ATPase structures reported were obtained of Rad54 from zebrafish and the archaeal organism Sulfolobus solfataricus (Sso) [72, 82]. Interestingly, the SsoRad54 ATPase sequence is among the most closely related sequences known to the yeast Mot1 ATPase sequence [49, 82], arguing that its structure serves as an especially accurate model for the overall fold of the Mot1 ATPase. Both Rad54 ATPases have a similar structural organization [72, 82], and the Rad54-DNA complex revealed residues required for DNA binding [82]. Moreover, the positioning of the RecA domains along duplex DNA supports the idea that Swi2/Snf2 ATPases travel along the minor groove of DNA, principally using interactions with one DNA strand [82]. If the Mot1 ATPase domain interacts with DNA similarly to other SF1 and SF2 enzymes, what would be the predicted DNA requirement for this interaction? The SsoRad54-DNA co-crystal structure shows that the ATPase domain interacts with primarily one strand of duplex B-form DNA extending for 12–15 bp, and the interactions are mediated primarily by domain 1A [82]. Comparison of the SsoRad54 and Mot1 primary sequences shows that a number of the DNA-binding residues in SsoRad54 are conserved in Mot1, and mutational analysis supports the role of Mot1 residues in TBP-DNA interaction [49]. However, Mot1 alone has no detectable DNA binding activity on its own [21, 32, 49, 83–85]. Instead, the interaction of Mot1 with DNA is readily demonstrated by the cooperative interaction between Mot1 and TBP on DNA, yielding a DNase I footprint that extends approximately two turns of DNA upstream from the TATA sequence [49, 84].

Remarkably, the DNA interaction length observed in the SsoRad54-DNA co-crystal structure is very similar to the length requirement for Mot1 binding to the TBP-DNA complex established from biochemical experiments [49, 84, 86]. DNA segments with insufficient length for Mot1 interaction are deficient in catalysis of TBP-DNA dissociation as well [84, 86]. Extensive analyses of the DNA requirement have not shown any significant dependence on the DNA sequence per se, again consistent with structural data showing that the RecA domains contact primarily the sugar phosphate backbone rather than bases. Although one study reported that Mot1 does not require a DNA extension flanking the TATA box [85], a large body of evidence employing different types of assays and methodologies, Mot1 mutational analysis, as well as different DNA templates, provides strong and self-consistent support for the DNA interaction and length requirement summarized here [32, 49, 84, 86]. In hindsight, the Mot1 DNA length requirement is relatively unsurprising given the structural evidence that shows a conserved mode of DNA or RNA interaction by SF1 and SF2 enzymes [57, 64]. Mot1/BTAF1 can stabilize binding of TBP to nonconsensus TATA sequences [85, 87]. In our view, this “relaxed” DNA binding specificity is the result of simple cooperativity in the interaction between Mot1, TBP and DNA. However, whether TBP interacts with DNA differently in the Mot1/BTAF1 ternary complex compared to TBP alone awaits structural analysis to define the details of the DNA interface.

2.2. Targeting of Mot1 to TBP

While all members of the Swi2/Snf2 family contain a well-conserved ATPase domain, their particular tasks in the cell are specified by additional domains that mediate interaction with substrate protein-DNA complexes, or other factors. The interaction with TBP occurs through the Mot1 N-terminal domain [22, 83, 88, 89]. The Mot1 N-terminus is composed of a series of 13 computationally identified HEAT repeats (Huntingtin, elongation factor 3, protein phosphatase 2A, target of rapamycin 1) that extend throughout the ~80 to ~150 kD region conserved among Mot1 homologues from different species [90–92]. HEAT repeats form alpha helical hairpins, and in proteins that possess multiple HEAT sequences, the hairpins typically stack on one another to form extended C- or sickle-shaped structures [93]. The predicted curved and extended shape for Mot1/BTAF1 is consistent with hydrodynamic measurements [48] and image reconstruction derived from electron microscopy of negatively stained single particles [94]. The elongated shapes of HEAT repeat proteins, exemplified by importin-beta [95] and the PR65 subunit of PP2A [96], provide extended surfaces for protein-protein interaction [93, 97, 98]. This explains why a relatively long segment of Mot1/BTAF1 N-terminal amino acid sequence is required for interaction with TBP [22, 84, 88]. HEAT repeat (and related repeat) proteins are also interesting structurally because their extended shapes and absence of distal contacts endow them with elastic properties [93, 99–101]. As discussed below, we propose that the inherent ‘springiness’ of the Mot1 N-terminus is an integral component of its catalytic mechanism.

Stable Mot1-TBP complexes can be isolated from cell extracts, and the Mot1-TBP interaction has an affinity in the nanomolar range [26, 27, 33, 85, 102, 103]. On the other hand, fluorescence recovery after photobleaching (FRAP) measurements reveal distinct recovery curves for TBP and Mot1, suggesting that little if any Mot1 and TBP are stably associated with one another in vivo [44]. A clear understanding of the extent and stability of the Mot1-TBP complex in vivo awaits additional experimental work.

4.1 “DNA-based” Mechanisms for Mot1 Action

The ATPase activity suggested early on that Mot1 might possess helicase activity or some related activity that drives a change in DNA conformation [36]. DNA strand separation activity was ruled out not only because Mot1 displays no helicase activity in standard strand displacement assays in vitro [36], but because interstrand DNA crosslinks do not abrogate Mot1’s TBP-DNA dissociation activity (Figure 2d) [48, 84]. An alternative is that ATP hydrolysis induces DNA twist or bulge propagation through the TATA box. Such a mechanism would provide a parallel with chromatin remodeling enzyme function [113–116]. To test this idea, single-stranded gaps were introduced in the DNA between the TBP-TATA complex and upstream DNA required for Mot1 binding and catalysis [84]. Here again, Mot1’s TBP-DNA dissociation activity was not affected, implying that while binding to flanking DNA is important, ATP hydrolysis does not induce torque on DNA in order to release TBP from the TATA box (Figure 2f) [84].

It was reported that Mot1 can readily remove TBP from a conformationally constrained mini-circle DNA template, a result which was interpreted to mean that Mot1 does not utilize DNA bending as an obligate part of the catalytic mechanism [84]. However, a 156 bp constrained mini-circle does not actually approximate the severity of the bend angle in the TBP-DNA complex. For this reason, whether the highly bent DNA in the TBP-DNA complex contributes to the Mot1 catalytic mechanism remains an open question. As discussed above, Mot1 was recently proposed to somehow exploit the ‘spring-loaded’ nature of the TBP-DNA complex to efficiently target TATA-containing TBP complexes for dissociation [50].

The final class of ‘DNA-based’ models posits that the Mot1 ATPase is a DNA tracking motor. In this view, the ATPase domain engages with duplex DNA and uses ATP hydrolysis to track either towards or away from the TBP-DNA complex (Figure 2e). Translocation towards TBP has been hypothesized to displace it from the TATA box by a snowplow mechanism [117]. Alternatively, translocation away from TBP might remove TBP by pulling it off its binding site on DNA. As discussed in section 2.1, ATP-driven DNA translocation is consistent with a wealth of structural and biochemical results for other ATPases in the enzyme family. While the available evidence strongly implicates translocation as part of the catalytic mechanism, this is not to imply that the highly bent TATA DNA, or unique properties of the Mot1-TBP-DNA complex, do not contribute to the TBP-DNA dissociation reaction.

4.2. Roles for TBP allostery or conformational change?

A very different possibility is that Mot1 uses ATP hydrolysis to induce a conformational change in TBP (Figure 2g). We disfavor this idea because, as discussed above, the HEAT repeats that form the TBP interaction surface and tether the ATPase domain to TBP are inherently elastic. Presumably, conformational changes in TBP relevant for Mot1 catalysis would need to be comparably dynamic in order to be put to use in the catalytic cycle. However, TBP is comprised of a single, small domain and a nonessential, flexible N-terminus. The numerous structures of TBP that have been reported bear a striking resemblance to one another with only very modest deviations in the relative orientations of secondary structural elements [107–109, 118, 119]. It is difficult to envisage how the conformationally pliable Mot1 enzyme might induce the kind of wholesale structural rearrangement in TBP structure that would likely be required to disrupt DNA binding.

Recently, evidence has emerged from analyses of other enzyme systems that allostery can occur in small single domain proteins without accompanying structural rearrangements [120, 121]. Although such effects challenge the conventional understanding of how allosteric effects occur, they have been explained in thermodynamic terms [121, 122]. These effects are reminiscent of the observation that a solvent-exposed surface of TBP can mediate rather dramatic effects on DNA binding, even though the surface is distal to the DNA binding surface [123]. Remarkably, this regulatory surface of TBP overlaps with surface residues implicated in Mot1 binding [89]. The combined observations lead to the intriguing but speculative idea that Mot1 binding per se to the ‘top’ surface of TBP can modulate TBP’s DNA binding behavior, perhaps predisposing it to ATPase mediated dissociation that occurs subsequent to Mot1-TBP-DNA ternary complex formation.

A conceptually related idea is that Mot1 activity is regulated in vivo by another factor. The TBP-interacting NC2 heterodimer is a good candidate [45, 102, 124]. A close correspondence has been observed between Mot1 and NC2 localization in vivo, and moreover, Mot1 and NC2 were co-associated with TBP in cell extracts [102]. These results extend prior work [39, 89, 125] demonstrating cooperation between Mot1 and NC2, and suggest that NC2 may demarcate or facilitate TBP-DNA complex dissociation by Mot1 in vivo [50, 102]. Mot1 can stabilize TBP binding to nonconsensus DNA sites, a result that was interpreted to mean that the Mot1-TBP complex has “relaxed” DNA binding specificity [85]. This could be due to the cooperative interaction between Mot1 and TBP, both of which interact with DNA, and/or it could be due to the ability of Mot1 to alter the molecular details of the TBP-DNA interaction. Distinguishing among these possibilities will probably require a high-resolution structure of the Mot1-TBP-DNA ternary complex.

5.1. Evidence for conserved structural organization and function of the Mot1 ATPase

Based on the structure of a Swi2/Snf2 enzyme Rad54, mutations in homologous residues in Mot1 were made that were predicted to affect its DNA binding and ATPase activities. As expected, the mutants were defective in coupling ATP hydrolysis to TBP displacement and those residues that were predicted to be important for ATP binding showed reduced TBP-stimulated ATPase activity [49]. These experiments support the idea that not only does the Mot1 ATPase have a similar structure as the SsoRad54 ATPase domain, but that Mot1 utilizes a conserved mechanism for ATP hydrolysis-coupled TBP-DNA disruption.

5.2. Evidence for two conformations of the Mot1 ATPase

Structures of SF1 and SF2 ATPases show the RecA domains in either a “closed” conformation, in which the ATP-binding catalytic cleft is properly formed, or an “open” conformation in which one RecA domain has undergone a large rigid body rotation with respect to the other and as a consequence, the ATP binding site does not exist [57, 82, 133]. In the crystal of the SsoRad54-DNA co-complex, the ATPase is in the open conformation, suggesting that the open and closed states represent snapshots of ATPase conformations along the normal catalytic path [82]. In support of this idea, the existence of open and closed conformational forms has been observed directly in solution [134]. This suggests that ATP binding and hydrolysis regulate the interconversion between the open and closed states (Figure 4a, b, c, e). Since DNA binds across the ATP catalytic cleft, RecA domain reorientation in this way would push on the minor groove, explaining how ATP hydrolysis is coupled to DNA translocation [57, 82]. In fact, biochemical evidence supports this general model as being applicable to Mot1. In solution, Mot1-TBP-DNA ternary complexes are of two types: ~60% are more stable than TBP-DNA alone (Figure 4b), whereas the remaining complexes are less stable than TBP-DNA alone (Figure 4d) [49]. Importantly, the ternary complexes with reduced stability were observed in the absence of ATP, implying that Mot1 can catalyze an ATP-independent TBP-DNA destabilization reaction [49]. A mutation in the hinge connecting the two RecA domains abolished the biphasic behavior, giving rise only to complexes with greater stability than TBP-DNA [49]. FRET experiments also revealed evidence for an ATPase conformational change that occurs in SsoRad54 after ATP hydrolysis but before ADP release [134]. This fits nicely with the observation that binding of ATP is insufficient for Mot1 to catalyze TBP-DNA dissociation; hydrolysis of ATP is critical for completion of the ATP-dependent reaction (Figure 4b, c, e) [89]. Taken together, the available results strongly support an ATP-driven conformational cycle for Mot1 that is mechanistically similar to cycles inferred for related enzymes.

5.3. Mot1 ATP hydrolysis rate and translocation

The ATP-independent destabilization of TBP-DNA by Mot1 was completely unexpected [49]. We suggest that when Mot1 binds to TBP-DNA, the ATPase can dock onto the upstream DNA (see section 2.1) in either the closed or open conformation. If the complex assembles in the closed conformation, ATP is not required for the dissociation reaction to proceed. In this case, we suggest that TBP-DNA dissociation occurs because an induced-fit of Mot1 to TBP-DNA destabilizes the TBP-DNA interface. If the complex assembles in the open conformation, ATP binding is required to drive the conformational transitions that result in TBP-DNA dissociation.

In the absence of ATP, there is no energy source to promote multiple rounds of the catalytic cycle, so if the ATP-independent reaction involves the same conformational changes as the ATP-dependent reaction, an implication is that TBP-DNA dissociation by stably bound Mot1 can probably be accomplished by just one round of ATP hydrolysis. This is consistent with observations of 10 bp displacements of the nucleosome by RSC under single ATP turnover conditions [130]. Comparison of the ATP hydrolysis rate with TBP-DNA dissociation rate indicated that as many as ~13 ATPs are hydrolyzed by Mot1 for each TBP-DNA complex dissociated [49]. The stoichiometry is undoubtedly inflated by ATP hydrolysis by free Mot1, but it is also possible that Mot1-mediated catalysis is relatively inefficient or that more than one ATP is required per dissociation event. An additional caveat is that the ATP-independent dissociation reaction is not observed using all TATA-containing DNA templates [86], so the predominant Mot1 reaction mechanism appears to be DNA sequence dependent on some level.

ATPases that interact with DNA move in one direction by tracking along one of the two DNA strands. Since DNA has an intrinsic symmetry, the tracking directionality is dictated by other interacting factors [64]. A wealth of information has emerged on how this occurs on a molecular level. Conceptually, the mechanism is akin to the inchworm model proposed by Yarranton and Gefter more than 30 years ago [135]. Presumably, the asymmetric binding of Mot1 to the TBP-DNA complex [84] is responsible for ATP-driven tracking on upstream DNA either toward or away from TBP bound to the TATA Box. Despite the large body of evidence that SF1 and SF2 enzymes are nucleic acid translocating enzymes, and that chromatin-remodeling enzymes in particular are DNA tracking enzymes, it’s been clear for some time that Mot1 does not track processively on DNA [117]. Short-range translocation, using triplex helix displacement assays for example, have also failed to reveal translocation activity (W-S. Park and D.T.A., unpublished observations). However, translocation of one or a few base pairs would not be detectable by these assays. This distinction in tracking ability can be understood in terms of the targeted substrate. Rather than reorganizing an extensive protein-DNA interface as required by a chromatin-remodeling enzyme, Mot1’s task is comparatively simpler. Displacement of TBP from DNA need not require a processive translocase because the TBP-DNA interface is much smaller; disruption of one or a few TBP-DNA interactions would be sufficient to induce dissociation of the TBP-DNA complex. Additionally, BTAF1 has been shown to regulate the DNA binding surface of TBP through its N-terminal HEAT repeats [22]. A pre-formed yeast Mot1-TBP complex does not bind DNA well, consistent with a role for Mot1 in regulating the TBP-DNA binding surface accessibility, and in this case the effect is regulated by ATP hydrolysis [49, 84]. Together, the results suggest that domains on Mot1 may regulate TBP-DNA binding or ensure irreversibility of TBP-DNA dissociation via interactions with TBP’s DNA binding surface.

5.4. Macromolecular springs and how translocation may be put to use

While models in which Mot1 dissociates TBP-DNA complexes by inducing DNA twisting or strand separation have been largely ruled out, it remains possible that DNA unbending facilitates the dissociation reaction [50] (see section 3). The release of the bent DNA in the TBP-DNA complex and its relaxation to a straightened form has been proposed to drive dissociation like the release of tension in a spring [50]. An alternative, and perhaps complementary idea, is that spring-like HEAT repeats that tether the Mot1 ATPase to TBP fulfill a similar function by storing elastic tension generated as the ATPase domain walks along DNA. As discussed in section 2.2, HEAT repeat proteins are inherently springy, and biochemical and computational data support the notion that the Mot1 N-terminus has such properties as well. We propose that the HEAT linker in Mot1 is not simply a passive connector of the ATPase to TBP, but that its stretchable and compressible character would allow the ATPase to translocate along DNA, and then displace TBP when a critical threshold of force is achieved. Remodelers can generate forces of up to ~12 pN [129]. Although an estimate is highly speculative, based on measurements of the spring-like behavior of ankyrin-B repeats [101], and assuming that the spring constants of HEAT and ankyrin repeats are similar, the HEAT repeats of Mot1 could stretch by ~0.7 nm in response to ATP-driven DNA translocation. This corresponds to a stepping distance of ~2 bp along DNA. Additionally, if the Mot1 ATPase behaves similarly to chromatin remodeling ATPases [49, 53, 60, 61, 89], the prediction is that ATP hydrolysis induces it to walk away from the TBP-DNA complex. This prediction is consistent with photocrosslinking results that show the Mot1 ATPase domain interacts primarily with the “top” strand of DNA [49] and a typical 3′ to 5′ translocation direction for SF2 ATPases [59–62, 64]. It is unknown if DNA translocation alone would be sufficient for TBP-DNA dissociation. However, even among enzymes that induce structural changes in their substrates as a result of ATP hydrolysis, nucleic acid translocation is fundamentally the mechanistic basis for the observed catalytic activity [136, 137].

In summary, based on the conserved structural organization and function of the ATPase domain and the biochemical evidence, the catalytic mechanism of Mot1 resembles the mechanism of other Swi2/Snf2 enzymes. As DNA translocation is a conserved feature of the ATPases of the Swi2/Snf2 family, we propose that the catalytic mechanism by which Mot1 displaces the TBP-DNA complex involves short range DNA tracking, which serves to pull or push TBP off its binding site on DNA. Additionally, the elastic nature of the Mot1 N-terminus that tethers the ATPase domain to TBP-DNA might contribute to the displacement reaction by storing energy until a dissociation threshold is reached.

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