Structural insights into regulation and action of SWI2/SNF2 ATPases
Highlights
► SF2 ATPases can be regulated by blocking nucleic acid binding surfaces. ► Domain organization of SF2 ATPase motors can be influenced by regulatory elements. ► Swi2/Snf2-specific subdomains are positioned to disrupt nucleic acid structure.
Introduction
Helicase-type proteins span several superfamilies that encompass functionally diverse collections of proteins involved in all aspects of nucleic acid processing, metabolism, and regulation [1]. Chromatin remodelers constitute one specialized family within helicase Superfamily 2 (SF2), and were originally named for their ability to alter the position and structure of nucleosomes. The ATPase motor, called SWI2/SNF2 after the first chromatin remodeler studied, has been found in a wide range of proteins, not all of which target the nucleosome but are aimed at disrupting distinct protein–nucleic acid complexes [2, 3]. Within the SWI2/SNF2 family, the ATPase motor is typically accompanied by multiple auxiliary domains, which presumably modify action of the ATPase through targeting and regulation.
Like all helicase Superfamily 1 (SF1) and SF2 ATPases, SWI2/SNF2 ATPases consist of two covalently linked RecA-like domains that form a bilobed motor (Box 1). The architecture of SF1 and SF2 ATPases has been extensively reviewed [1, 4, 5]; therefore, we will focus on particular elements relevant to regulation and DNA binding of the ATPase motor. As observed in many structural examples of SF1 and SF2 ATPases, unique domains or subdomains are often found closely associated with the bilobed motor, and can be attached at the amino-terminus or carboxyl-terminus, or protrude as extended loops from one or both of the RecA-like domains. These unique domains have been shown to aid the ATPase motor in binding to particular substrates, or participate in distortion of bound nucleic acids [4].
To date, crystal structures of only a few representatives containing the SWI2/SNF2 ATPase motor have been solved: Rad54 from zebrafish [6••] and Sulfolobus solfataricus [7••], Escherichia coli Rap1 [8•], and Saccharomyces cerevisiae Chd1 [9••]. These structures have revealed the common structural features of SWI2/SNF2 ATPases and provided several examples of how the ATPase motor interacts with auxiliary domains. We begin with a description of how the SWI2/SNF2 ATPase motor of the Chd1 remodeler is negatively regulated by a pair of chromodomains that can block the DNA-binding surface. Although no SWI2/SNF2 ATPases have yet been solved in an active, hydrolysis-competent configuration, the S. solfataricus Rad54 structure in complex with duplex DNA demonstrated that the first ATPase domain (1A) contacts nucleic acid at the same location as observed in other SF2 ATPases. To extend our structural understanding of SWI2/SNF2 proteins, we will draw parallels with the well-studied DEAD-box RNA helicase family, a distinct but related family of SF2 ATPases for which many structures have been solved in various activated and inhibited states. We conclude with a structural comparison of SWI2/SNF2-specific inserts to nucleic acid disrupting elements found in other SF2 ATPases. The sequence and structural conservation of these inserts suggest that translocation by SWI2/SNF2 ATPases may be accompanied by localized distortion of the DNA duplex.
Section snippets
Keeping false substrates at bay: blocking the nucleic acid binding site
The crystal structure of the chromodomain-ATPase portion of Chd1 revealed an apparent autoinhibited organization, where the double chromodomains pack against both halves of the ATPase motor, spanning the central cleft (Figure 1a [9••]). The conformation of the ATPase motor appears to be in an inactive form, which like many SF2 ATPases without nucleic acid substrates, displays an opened conformation and thus lacks the close association of helicase motifs across the central cleft that are
Influencing RecA-like domain orientation as a means of regulating activity
In addition to blocking the DNA-binding site, SF2 helicase activity may be influenced by preventing proper closure of the RecA-like domains. For the PDCD4–eIF4A complexes, interactions of PDCD4 with the ATPase cleft not only block nucleic acid binding surfaces but also appear to stabilize a splayed open conformation of the helicase incompatible with hydrolysis [16•, 17•] (Figure 1b). For Chd1, the opened organization of the ATPase motor coupled with contacts made by chromodomains suggests that
Helical subdomains of SWI2/SNF2 ATPases appear positioned to distort duplex DNA structure
The ATPase motors of chromatin remodelers are distinguished by the presence of helical subdomains (1B and 2B) inserted in each of the RecA-like lobes [2, 3, 6••, 7••] (Figure 3a). When the two lobes of the ATPase motor are modeled in a hydrolysis-competent closed state, these helical subdomains cluster together at one edge of the predicted DNA-binding site. As previously suggested, the locations of these subdomains may imply a direct interaction with DNA [2, 3, 6••, 7••]. Interestingly, an
Concluding remarks
Despite only a few structural examples of SWI2/SNF2 ATPases, a wealth of structural data for related SF2 ATPases, particularly those from the DEAD-box family of RNA helicases, has enabled predictions for how auxiliary domains such as the Chd1 chromodomains can influence activation of the ATPase motor. While comparisons between families such as SWI2/SNF2 and DEAD-box helicases will continue to be informative, significant progress in understanding the molecular mechanisms utilized by SWI2/SNF2
Note added in proof
Two recent advances in understanding how domains outside the SWI2/SNF2 ATPase motor engage their targets have been provided by crystal structures of the N-terminal TBP-binding domain of Mot1 in complex wth TBP [50] and the Isw1 DNA-binding domain bound to Ioc3 and DNA [51].
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Ilana Nodelman and other members of the Bowman lab for critical comments and discussions. This work was supported by a grant from the National Institutes of Health (R01 GM084129).
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