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Review
, 21 (6), 728-34

Understanding Histone Acetyltransferase Rtt109 Structure and Function: How Many Chaperones Does It Take?

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Review

Understanding Histone Acetyltransferase Rtt109 Structure and Function: How Many Chaperones Does It Take?

Sheena D'Arcy et al. Curr Opin Struct Biol.

Abstract

Rtt109 (Regulator of Ty1 Transposition 109) is a fungal-specific histone acetyltransferase required for modification of histone H3 K9, K27 and K56. These acetylations are associated with nascent histone H3 and play an integral role in replication-coupled and repair-coupled nucleosome assembly. Rtt109 is unique among acetyltransferases as it is activated by a histone chaperone; either Vps75 (Vacuolar Protein Sorting 75) or Asf1 (Anti-silencing Function 1). Recent biochemical, structural and genetic studies have shed light on the intricacies of this activation. It is now clear that Rtt109-Asf1 acetylates K56, while Rtt109-Vps75 acetylates K9 and K27. This reinforces that Asf1 and Vps75 activate Rtt109 via distinct molecular mechanisms. Structures of Rtt109-Vps75 further imply that Vps75 positions histone H3 in the Rtt109 active site. These structures however raise questions regarding the stoichiometry of the Rtt109-Vps75 complex. This has ramifications for determining the physiological Rtt109 substrate.

Figures

Figure 1
Figure 1. Rtt109 acetylates histone H3 at K9, K27 and K56
(a) Rtt109-Vps75 acetylates K9 and K27 in the H3 tail (dotted line), while Rtt109-Asf1 acetylates K56 (shown as sticks) in the H3 histone-fold domain. Yeast H3 (blue) and H4 (green) are shown in cartoon (taken from nucleosome PDB 1ID3). (b) Rtt109 adopts a similar conformation when free (apo) or bound by Vps75. Shown is a cartoon superposition of free (PDB 3CZ7) and Vps75-bound Rtt109 (PDB 3Q66 and 3Q33) colored according to secondary structure. The acetyl-CoA and residues K290Ac, D287 and D288 are shown as sticks. Abbreviations: Res. – residues.
Figure 2
Figure 2. Interfaces observed in Vps75-Rtt109 at a 2:1 [Su et al.] (a) and 2:2 [Tang et al.] (b) stoichiometry
(a), (b) Cartoon representation of the Rtt109 (red or pink) and Vps75 (blue or pale blue) complex [PDB 3Q66 in (a) and 3Q33 in (b)]. Bottom views are 90° rotations of top views and key interfaces are boxed. The asymmetric unit is shown in (a), while the asymmetric unit and a Rtt109-Vps75 pair related by a crystallographic 2-fold symmetry axis are shown in (b). Interface III is not found in the 2:2 complex (broken box). (c) Description of the Rtt109 and Vps75 regions involved in interfaces I, II and III.
Figure 3
Figure 3. Conformational differences between Vps75-Rtt109 at a 2:1 and 2:2 stoichiometry
Cartoon superposition (via a single Vps75 chain) of Vps75 alone (PDB 3DM7 chain a – yellow) and Rtt109-Vps75 (PDB 3Q66 chains a and c – blue and 3Q33 – orange). (a) Compared to free Vps75, the Vps75 dimerization helix is kinked in the 2:2 complex and arcs downwards in the 2:1 complex. Rtt109 chains are shown in white. (b) Rtt109 is shifted ‘outward’ in the 2:2 complex compared to the 2:1 complex. Arrows indicate example secondary structure shifts, and Vps75 chains are shown in white. Interface I and II remain intact.

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