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Published in final edited form as: Curr Opin Struct Biol. 2012 Mar 23;22(2):225–233. doi: 10.1016/j.sbi.2012.02.007

Swi2/Snf2 remodelers: hybrid views on hybrid molecular machines

Karl-Peter Hopfner 1,2,*, Christian Gerhold 1, Kristina Lakomek 1, Petra Wollmann 1
PMCID: PMC3323801  NIHMSID: NIHMS366253  PMID: 22445226

Summary

Swi2/Snf2 (switch / sucrose non-fermentable) enzymes form a large and diverse class of proteins and multiprotein assemblies that remodel nucleic acid:protein complexes, using the energy of ATP hydrolysis. The core Swi2/Snf2 type ATPase domain belongs to the “helicase and NTP driven nucleic acid translocase” superfamily 2 (SF2). It serves as a motor that functionally and structurally interacts with different targeting domains and functional modules to drive a plethora of different remodeling activities in chromatin structure and dynamics, transcription regulation and DNA repair. Recent progress on the interaction of Swi2/Snf2 enzymes and multiprotein assemblies with their substrate nucleic acids and proteins, using hybrid structural biology methods, sheds light onto mechanisms of the complex chemo-mechanical remodeling reactions. In the case of Mot1, a hybrid mechanism of remodeler and chaperone emerged.

The Swi2/Snf2 ATPase: A versatile motor

“Remodelers” are diverse molecular machines that use the energy of ATP to disrupt or remodel protein:nucleic acid complexes, most notably nucleosomes but also others such as transcription factors and RNA polymerase. The shared chemo-mechanical “engine” of remodelers is a Swi2/Snf2 ATPase, which possesses a Swi2/Snf2 ATPase domain along with other domains that target, regulate and/or mechanistically couple the ATPase domain with the substrate in the remodeling reaction (Fig. 1). Swi2/Snf2 domains form a subgroup among SF2 helicases/translocases, which also include DEAD box RNA helicases, DNA helicases, and innate immune sensors [1]. SF2 enzymes have at least 12 characteristic sequence motifs that are involved in ATP binding and hydrolysis or interaction with the nucleic acid substrates. ATP binds between and repositions the two RecA-like (sub)domains of the SF2 fold, leading to a conformational shift in nucleic acid binding motifs [2]. Depending on the SF2 family, the conformational switch can grip or bend nucleic acids without translocation, but often leads to an “inchworm” like movement along nucleic acids.

Fig. 1.

Fig. 1

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Swi2/Snf2 ATPases. (a) Domain organization of selected Swi2/Snf2 ATPases. (b) The Swi2/Snf2 ATPase domain consists of a DExx (RecA like 1) and a HELICc (RecA like 2) domain that together have at least 12 characteristic sequence motifs with roles in nucleic acid and/or nucleotide binding or hydrolysis. (c) Selected structures of adjunct domains in Swi2/Snf2 ATPases in complex with their substrates. (d) Functions of respective domains present in various remodelers.

A variety of studies indicate that Swi2/Snf2 domains use ATP to track along the minor groove of dsDNA [3–5]. This tracking can go over considerable distances as in the case of Rad54 [6]. For RSC, a large nucleosome remodeling complex, optical tweezer experiments revealed for instance a translocation processivity of about 35 bp with a step size of approximately 2 bp and a rate of roughly 25 bp/s on dsDNA, applying substantial mechanical force (30 pN) that suffices to disrupt DNA-histone interactions after bulging the DNA during initiation [7].

While several structures of the Swi2/Snf2 domains alone, bound to DNA and in complex with accessory domains have been determined [3,8–10], it has not yet been worked out how ATP dependent conformational changes in the Swi2/Snf2 domain propel the enzyme in a directional manner along the minor groove. However, it is likely that the mechanism bears similarity to the single-base(pair) stepping mechanism of SF1 helicases [11].

Structural and functional versatility

Despite their conserved motor domain, Swi2/Snf2 enzymes execute a broad spectrum of remodeling reactions and a key question is how the force generated by the motor activity is used to disrupt substrate protein complexes. The most complex family of Swi2/Snf2 enzymes are protein assemblies that alter the position or composition of nucleosomes and are currently grouped into SWI/SNF, ISWI (imitation switch), CHD/Mi-2 and INO80 (inositol auxotroph mutant 80) families. SWI/SNF and the related RSC (Remodeling the structure of chromatin) complexes disrupt nucleosomes either through repositioning or dissociation [12,13], while equally complex INO80 and the related SWR1 exchange histone H2AZ and H2A variants [14,15]. Chd1 (Cchromodomain-helicase-DNA-binding protein 1) and ACF/ISWI remodeler slide nucleosomes and catalyze nucleosome spacing [16,17]. Together, the combination of these activities ensures a dynamic nature of chromatin, and results from chromatin reconstitution procedures and analysis of DNA double-strand break repair hint at considerable collaboration of remodelers in vivo [18,19].

Other Swi2/Snf2 enzymes have a much simpler architecture. For instance, the single subunit remodeler Mot1 (modifier of transcription 1, denoted BTAF1 in humans) acts on the transcription initiation factor TBP (TATA-box binding protein) to modulate TBP`s association to promoter DNA [20]. The bacterial Swi2/Snf2 remodeler RapA, which recycles RNA polymerase, is functional as a single polypeptide chain and has even been structurally determined as whole (Fig. 2a) [10]. Other remodelers include DNA repair enzymes Rad54, Cockayne Syndrome protein B and Rad5, Rad16 and HLTF, but will not be discussed further. A remarkable Swi2/Snf2 “remodeler” is HARP (HepA-related protein), which acts as an annealing helicase [21].

Fig. 2.

Fig. 2

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Swi2/Snf2 enzyme architecture and model for nucleosome spacing by ISWI. (a) Crystal structure of E. coli RapA, the only full length Swi2/Snf2 enzyme structure [10]. The positions of the ATPase lobes 1A and 1B (DExx domain) as well as 2A and 2B (HELICc) are indicated. (b) Crystal structures of S. cerevisiae Chd1 domains. Left: SANT (dark green) and SLIDE (light green) domains bound to DNA (brown) [39]. Right: The tandem chromodomains (pink) block the DNA binding site on the Swi2/Snf2 ATPase domain. (c) Crystal structure of yeast Isw1a(ΔATPase) in complex with DNA (brown) [37]. According to the proposed dinucleosome model of remodeling (cf. (d)) the two DNA duplexes bound by the yIoc3 subunit (yellow) and the SANT (dark green) and SLIDE (light green) domains of yIsw1, represent external- and internal-linker DNA, respectively. (d) Dinucleosome model of remodeling by yeast Isw1a [37]. Nucleosome spacing by Isw1a is proposed to occur by one of the two schematically represented alternative mechanisms with either flexible linker DNA or flexible protein linker between Isw1`s ATPase domain and the HSS (HAND-SAND-SLIDE) assembly. In both scenarios, the Swi2/Snf2 domain slides the mobile nucleosome and pulls together the dinucleosome until the HSS-HL (HSS – helical linker) module between the two nucleosomes prevents further movements.

A key feature of remodelers is the correct targeting of the Swi2/Snf2 motor to the substrate. An emerging targeting module is the SANT-SLIDE (comprised in switching-defective protein 3, adaptor 2, nuclear receptor co-repressor and transcription factor TFIIIB / SANT-like ISWI) domain combination, which recognizes the nucleosome and internucleosomal DNA in ISWI type remodelers and is sufficient for nucleosomal DNA binding [22]. The SANT-SLIDE module targets nucleosomal substrates most likely based on a continuous sampling mechanism in a seconds-to-minutes-timescale [23]. This model is in accordance with the high abundance of ISWI complexes in the nucleus and their extreme mobility. They accumulate within tens of seconds at DNA damage sites upon UV exposure [24].

Additional recruitment to epigenetic marks is mediated for instance by tandem chromodomains of Chd1 or by human BPTF (bromodomain and PHD finger-containing transcription factor) - a subunit of the ISWI homologue NURF (nucleosome remodeling factor) complex. Here a PHD finger with an adjacent bromodomain recognizes nucleosomes that are trimethylated at H3K4 and also bear an acetyllysine in their H4 histone tail [25]. A notable set of subunits in SWI/SNF and INO80 type remodelers are actin related subunits. INO80 complexes that lack histone binding subunits Arp4 and Arp8 (actin-related proteins 4 and 8) fail to bind to DNA and to remodel nucleosomes and mammalian INO80 complexes require Arp8 for targeting to sites of DNA damage [26–28]. Together with other DNA-binding subunits such as human YY1, Arps could serve as nucleosome recognition modules targeting INO80 to the appropriate responsive elements in different contexts [29,30].

Targeting is not limited to the classic epigenetic marks and nucleosomes and more and more principles emerge. Recently, a functional poly(ADP-ribose) (PAR) binding macrodomain has been identified in the CHDL-type remodeler Alc1 (amplified in liver cancer 1), which could remodel chromatin after recruitment by ADP-ribosylation of DNA damage sites [31,32].

Towards a high resolution nucleosome remodeler structure and mechanism

A key question in the field is, how the ATP dependent DNA translocation activity is structurally coupled to substrate remodeling. Progress towards this goal has recently been achieved on the ISWI- and Chd1-type remodelers (Figs. 2b,c,d) although the molecular mechanism of chromatin remodeling applied by ISWI-family members is still under debate. In general, members of the ISWI/ACF-family generate regular nucleosomal arrays by shifting nucleosomes until the linker DNA becomes too short. Yeast Isw2 for instance binds around 20 bp of extranucleosomal DNA directly flanking the nucleosome on its entry site [33]. The remodeling process by Isw2 can be classified into distinct stages. Kinetic data uncovered a slow initiation process, which might be essential to make yIsw2 competent for DNA translocation upon binding. It could correspond to the second step of a two-step DNA binding mechanism [34], in which a first conformational switch of ISW2 upon ATP-binding enhances its association with extra- and nucleosomal DNA at the entry site and dyad axis. ATP hydrolysis and the resultant formation of a stable and processive ISW2:substrate nucleosome complex [35] leads to extended interactions with nucleosomal DNA. The dissociation of the catalytic subunit`s translocase domain from the nucleosome is needed for effective nucleosome shift and goes along with a conformational rearrangement initiated upon the percipience of the shortening DNA strand [33].

A combination of electron microscopy, biochemical and biophysical studies revealed the presence of two ACF complexes bound at nucleosomes and biochemically found that two ACF complexes cooperate and take turns to move a nucleosome [16]. An accompanying study using advanced single molecule FRET analysis showed that ACF translocates for approx. 7 bp, until it pauses. Nucleosomes were repositioned in steps closer to 3 bp [36]. Interestingly, all steps – binding, sliding, pausing – were ATP-dependent. This remarkably broad role of ATP indicates that the conformational cycle of the Swi2/Snf2 domain has functions apart from mere dsDNA groove tracking.

While these studies provided insights on the action of the Swi2/Snf2 domain at the nucleosome, it remains unclear how nucleosomes are actually spaced. On the basis of a hybrid approach combining Isw1a-DNA complex crystal and Isw1a-nucleosome EM structures with site-specific photo-crosslinking experiments on Isw1a-nucleosome assemblies, Richmond and colleagues showed that the substrate for remodeling by Isw1a is in fact a dinucleosome and provided an intriguing model for nucleosome spacing (Figs. 2, 4b) [37]. The complex of HAND-SANT-SLIDE (HSS) domains with Ioc3 form a molecular ruler module that ensures correct nucleosome spacing by binding between two nucleosomes (Fig. 2). The Swi2/Snf2 domain binds the nucleosomal DNA, and its translocase activity helps to reel in linker DNA to move the mobile closer towards the static nucleosome until the HSS-Ioc3 module stops further translocation. A remarkable outcome of the study is also the implication of a potential sequence preference for the Ioc3 subunit that could be important to reposition nucleosomes at promoter regions. In contrast to the dimeric motor ACF, Isw1a appears to work as single motor. Thus, the precise stoichiometry of ISWI factors on nucleosomal arrays needs to be studied further.

Fig. 4.

Fig. 4

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Comparative multistep remodeling models. (a) Mot1. (I) TBP surface recognition of Mot1 by HEAT repeat loops (I) activates the ATPase activity of the enzyme and DNA binding by TBP (II). Groove tracking of the ATPase domain generates torque that weakens TBP:DNA interactions, leading to TBP displacement from the DNA (III). The Mot1 latch acts as a chaperone to prevent TBP from binding to DNA and from dimer formation (IV). (b) Isw1a and Chd1. (I) Nucleosomal linker-DNA duplexes are bound by the yIoc3 subunit and by the SANT domain of yIsw1. (II) Yeast Chd1`s chromodomains regulate the DNA binding site [9]. (III) Remodeling by yeast Isw1a by the dinucleosome spacing model (see Fig. 2d for details). (IV) Nucleosome remodelers may have intrinsic chaperone functions similar to Mot1, however there is a dedicated chaperone network for histones to maintain correct delivery to sites of remodeling and chromatin formation.

Recently, structures of Chd1`s DNA-binding domain (DBD) have been determined alone [38] and bound to a dodecameric DNA duplex [39]. These structures revealed that the DBD is composed of a SANT and a SLIDE domain strikingly reminiscent of ISW1, a feature that was not obvious from the sequence. Hence, this module appears to be more broadly utilized by Swi2/Snf2-ATPases. However, based on the resemblance concerning SANT and SLIDE domains, the grouping of CHD1/Mi-2 and ISWI into different families rather than the same should perhaps be reconsidered.

Regulation of the Swi2/Snf2 ATPase

Numerous enzymes are regulated by internal regulatory or repressor domains. The crystal structure of yeast Chd1`s tandem chromodomains together with the Swi2/Snf2 domain was determined and established this principle now within the Swi2/Snf2 family [9]. The most remarkable aspect of this study was the observation that the double chromodomains block DNA binding and activation of the Swi2/Snf2 ATPase in the absence of nucleosome substrates (Fig. 2). Indeed, removal of the chromodomains resulted in a greatly enhanced ATPase activity. Earlier studies showed that the human CHD1 double chromodomains target the lysine 4-methylated histone H3 tail (H3K4me), a hallmark of active chromatin [40]. However, the chromodomains of CHD1 in flies are not essential for chromatin localization of the enzyme but rather for enzymatic activity [41]. It is possible that CHD1 is targeted by other means, yet recognition of methylated lysine tails leads to activation of the Swi2/Snf2 ATPase at the target. Allosteric regulation may not be limited to chromodomains: a newly identified SnAC (Snf2 ATP coupling) domain has been shown to influence ATP hydrolysis of the Swi2/Snf2 domain as well [42], so we expect to see more of these internal regulatory mechanism of the ATPase activity. In any case, these results showed that internal repression or regulation of the ATPase could be an important feature to ensure that only the correct substrate DNA is bound by the Swi2/Snf2 motor, thereby enhancing specificity of the enzyme.

Mot1:TBP complex reveals hybrid remodeler-chaperone features

Given the prevailing scarcity of crystal structures of proteins bound to nucleosomes, progress towards the atomic structure of a remodeler:substrate complex has been obtained with Mot1 (Fig. 3a). Mot1 does not act on nucleosomes but on the transcription factor TBP. Besides the Swi2/Snf2 domain, Mot1 possesses a long N-terminal region that consists of HEAT (Huntingtin, elongation factor 3, protein phosphatase 2A, lipid kinase TOR) repeats and mediates interaction with TBP.

Fig. 3.

Fig. 3

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Hybrid remodeler - chaperone. (a) Crystal structure of the HEAT domain of Encephalitozoon cuniculi Mot1 (yellow) in complex with its substrate TBP (grey). Loops of the HEAT domain and the latch are highlighted in pink. (b) Highly conserved acidic loops of Mot1 are important for recognition of TBP`s convex surface. (c) Chaperone activities by the Mot1 latch, which blocks the hydrophobic site on TPB that binds DNA or another TBP molecule in forming dimers. (d) A hybrid methods approach. The principle is to combine information from different structural methods, typically X-ray crystallography, homology modeling and electron microscopy. Interactions constraints provided by e.g. crosslinking studies and mass spectrometry can help put together the individual pieces of high resolution structures in the EM 3D reconstruction.

Mot1 was identified as repressor of transcription by removing TBP from TATA boxes, but new results suggest that it can also act as activator of transcription [43,44]. In this regard, Mot1 could dissolve “inactive” TBP bound to NC2 (negative cofactor 2), thus liberating active TBP [45]. However, one interesting finding is that Mot1 creates a dynamic TBP pool that helps TBP to diffuse from TATA promoters to TATA less promoters [46,47].

The Mot1-TBP system offers a unique simplicity for a hybrid approach to elucidate a complete remodeler architecture (Fig. 3a). In the recently solved crystal structure of the HEAT domain of Mot1 in complex with TBP, Mot1 wraps one half of the saddle shaped TBP [48]. Critical for initial recognition are highly conserved, mostly acidic residues located on loops of the HEAT domain that contact TBP`s convex surface, a region that is also accessible in a DNA-bound form of TBP (Fig. 3b). This region can also be occupied by higher assemblies of the transcription initiation complexes, suggesting a mode of restricting Mot1’s activity to only a subset of TBP complexes.

An intriguing second binding site is located in the concave surface of TBP, evoking an interaction of a long Mot1 “latch” domain that directly competes with DNA binding and TBP self-dimerization (Fig. 3c). As a consequence, TBP does not form a dimer when bound to Mot1 and the observed complex is necessarily a “product” complex, i.e. after the remodeling reaction. These unexpected results identify Mot1 not only as remodeler but also as chaperone to prevent (re)formation of TBP:DNA or TBP:TBP complexes.

Mot1`s ATPase contacts the DNA major groove upstream the TATA region [49]. Still under debate is whether ATP hydrolysis is used to move Mot1 towards or away from the TBP-DNA complex. However, in both scenarios the motor activity would generate force that leads to a conformational change in the HEAT repeats. Based on their notable flexibility and springiness these protein modules are in principle suited to store the energy of a few ATP driven groove tracking steps until a certain threshold leads to a rapid stroke that passes the energy towards TBP displacement.

At present, one draft is a multistep recognition - activation - remodeling - chaperone model for the action of Mot1 on TBP comparable with lessons from the research on ISWI and Chd1 (Fig. 4): After initial recognition of the surface of TBP and perhaps allosteric activation of the ATPase, torsional force generated by the Swi2/Snf2 domain on upstream DNA might be sufficient to weaken the TBP-DNA interface, allowing the latch to be inserted to inhibit TBP rebinding to the DNA. In this regard Mot1 could also act as an escort factor for TBP around the nucleus. Chaperone activities may also be part of e.g. SWI/SNF type remodelers, but more research needs to be done to understand this type of activity in a broader context. However, it is well known that histones are delivered by an intricate network of dedicated histone chaperones (reviewed in [50]), so partial nucleosomes and unincorporated histone dimers might require intrinsic chaperone activities of large multisubunit remodelers.

Outlook

In the past couple of years, substantial progress in both enzymatic and structural approaches led to insights in the functional and structural coupling of the ATPase motor with other functional modules of remodelers, resulting in mechanistically more detailed models of the intricate chemo-mechanical reactions. Single-molecule studies using FRET or optical tweezers shed light on steps of the reaction and properties of the enzymes that are difficult if not impossible to reveal with bulk biochemistry. From a structural point of view, hybrid methods approaches typically combining electron microscopy of remodelers alone or in complex with substrates together with crystal structures of substantial submodules emerge as one way to go (Fig. 3d). This has proven quite powerful for Mot1 and Isw1 remodelers, because a substantial part of protein could be crystallized, and structural information for the missing domains is available from homology models, to place into and interpret the EM density maps.

It is much more difficult to address the structure of the more complex SWI/SNF and INO80 type remodelers. Nevertheless, several of these assemblies have been studied with and without nucleosomes by electron microscopy (reviewed in [51]). Although the resulting 3D reconstructions give interesting insights into shape and nucleosome binding cavities, they do not yet allow the interpretation with atomic models or placement of domains. A promising line to complement the EM studies and to help placing domains is to provide additional structural information such as crosslinking and mass spectrometry [52]. Having these powerful methods in place, we look forward to a more detailed understanding of the mechanistic architecture of the complex remodeler in the years to come.

Highlights.

  • ➢

    Swi2/Snf2 proteins/multiprotein assemblies remodel nucleic acid-protein complexes.

  • ➢

    Core Swi2/Snf2 ATPase domain is a structurally and functionally versatile motor.

  • ➢

    Hybrid methods pave the way towards nucleosome:remodeler structures & mechanisms.

  • ➢

    The remodelers Mot1, Chd1 and Isw1 use different ATP-driven multistep mechanisms.

  • ➢

    Mot1 employs a hybrid mechanism of remodeler and chaperone.

Acknowledgements

Work on remodelers and related ATPases in K-P H’s laboratory is supported by SFBs 646 and 684 of the German Research Council (DFG), by the research cluster CIPSM of the German Excellence Initiative and by NIH (U19AI083025) and by GRK1721.

Footnotes

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