Understanding histone acetyltransferase Rtt109 structure and function: how many chaperones does it take?
Graphical abstract
Highlights
► Histone chaperones Vps75 and Asf1 stimulate Rtt109 acetyltransferase toward histone H3 approximately 100-fold. ► Rtt109-Asf1 acetylates H3 K56, while Rtt109-Vps75 acetylates H3 K9 and K27. ► Auto-acetylation of Rtt109 at K290 is essential and is not influenced by Vps75. ► Based on structural work, the stoichiometry of Vps75-Rtt109 is uncertain; it may be 2:1 or 2:2. ► Vps75 imports Rtt109 into the nucleus, stabilizes Rtt109, and positions H3 for acetylation by Rtt109.
Introduction
Histone acetylation is a crucial regulatory mechanism of DNA-dependent processes such as transcription, replication and repair. It involves histone acetyl-transferase enzymes (HATs) that transfer an acetyl moiety from acetyl-CoA to the ɛ-amine group of a histone lysine residue. The cell contains several HATs, for example Gcn5 (General control nonderepressible 5) (KAT2) (lysine acetyl-transferase), p300/CBP (CREB-binding protein) (KAT3A/B) and Tip60 (Tat interactive protein 60) (KAT5), which between them acetylate different residues on the four core histone proteins [1, 2]. A recurrent feature of HATs is their presence in protein complexes with constituents that regulate their activity and substrate selectivity. Regulation prevents uncontrolled histone acetylation causing aberrant DNA metabolic events. The molecular underpinning of such regulation is challenging to decipher as it requires genetic, biochemical and structural approaches. This review will focus on recent developments relating to the HAT, Rtt109 (Regulator of Ty1 Transposition 109) (KAT11), particularly the molecular details of its interaction with and regulation by histone chaperone, Vps75 (Vacuolar Protein Sorting 75).
Section snippets
Rtt109 substrates
Rtt109 is a fungal-specific HAT historically associated with acetylation of histone H3 K56 (H3 K56Ac) [3, 4, 5]. Recent data, however, also establish H3 K9 and K27 as bona fide Rtt109 targets in yeast [6, 7]. Rtt109-dependent K9Ac and K27Ac eluded detection as unlike K56, these residues are also acetylated by Gcn5 [8]. Residues K9 and K27 are in the H3 disordered tail, while residue K56 is in the H3 histone-fold domain (Figure 1a) [9]. As such, Rtt109 cannot acetylate K56 on H3 that is a
Rtt109 activation – Vps75 versus Asf1
A well-established and intriguing feature of Rtt109 is its stimulation by binding partners Vps75 and Asf1 (Anti-silencing Function 1) [4, 10]. Vps75 and Asf1 are structurally unrelated histone chaperones that interact with histone (H3-H4)2 tetramer and H3-H4 dimer, respectively [15, 16]. The interactions between Vps75/Asf1 and H3-H4 have nanomolar affinity, ten times stronger than that between Rtt109 and H3-H4 [17, 18]. However, both Vps75 and Asf1 enhance the catalytic activity of Rtt109,
Rtt109 catalytic mechanism
Determining how histone chaperones activate Rtt109 ultimately requires insight into Rtt109 catalytic mechanism. Such insight has been gleaned from biochemical analyses [20•, 21•, 23] performed in the wake of the three Rtt109 crystal structures (Figure 1b) [19, 24, 25]. The structures of Rtt109 revealed an overall fold similar to the p300/CBP HAT domain, albeit with a non-conserved active site [19, 24, 26]. The structures also uncovered an acetylated lysine residue (K290) in the vicinity of the
Rtt109-Vps75 structures
Insight into Rtt109 has also emerged from recent crystallographic analysis with Vps75 [20•, 22••, 27•]. Three independent groups have reported a total of five Rtt109-Vps75 structures, with only two of the structures being from the same crystal form (Table 1). Notably, the data obtained by Kolonko et al. are of poor resolution, limiting structural detail and preventing refinement [20•]. Collectively the remaining structures reveal three potential interfaces between Rtt109 and Vps75 (interface I,
Future directions
Regardless of the outstanding issues relating to the Rtt109-Vps75 structures, they imply that Vps75 stimulates Rtt109 activity through positioning the histone H3 substrate. As such, there is a clear demand for a more molecular view of Vps75-histone complexes. Initial work with Vps75 homolog Set, clearly paves the way [29]. It will be interesting to see if Vps75 physically blocks K56. It will also be intriguing to determine why Vps75 paralog Nap1 (Nucleosome assembly protein 1) can bind to but
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
S.D. and K.L. are supported by the Howard Hughes Medical Institute. K.L. is also supported by the NIH (GM067777 and GM088409). We thank members of the Luger laboratory for helpful discussion.
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2021, International Journal of Biological MacromoleculesCitation Excerpt :It promotes genome stability. Rtt109 originates from S. cerevisiae and is responsible for H3K56 acetylation (Lysine K56 on histone 3) in coordination with histone chaperones that include Asf1 or and Vps75 [48,49]. The domain of Rtt109's is similar to that of p300.
Multisite Substrate Recognition in Asf1-Dependent Acetylation of Histone H3 K56 by Rtt109
2018, CellCitation Excerpt :In S. cerevisiae, Rtt109 forms an obligatory complex with another histone chaperone, Vps75. A school of thought proposes that Asf1 functions in H3K56ac through direct binding to Rtt109, perhaps via an allosteric mechanism much like that of Vps75 (Berndsen and Denu, 2008; D’Arcy and Luger, 2011; Kolonko et al., 2010; Tsubota et al., 2007). An alternative proposal is that Asf1 functions to present the H3-H4 complex for acetylation by Rtt109, but a precise mechanism has been elusive (Han et al., 2007b).
Chaperone-mediated acetylation of histones by Rtt109 identified by quantitative proteomics
2013, Journal of ProteomicsCitation Excerpt :These two chaperones are not structurally related but they both bind to new H3/H4 molecules [25,26]. While Rtt109 interacts only weakly with Asf1, crystal structures revealed the formation of a tight and stable complex with the chaperone Vps75 [27–29]. The chaperones are required to present the substrate in a distinct orientation that confers target specificity to Rtt109.