Three Superfamilies of KATs

K-acetylation is reversible and its level is dynamically controlled by KATs and KDACs (Fig. 1). Since the identification of the very first KATs in the mid-1990s, various mammalian proteins have been discovered to possess such an enzymatic activity (Sterner and Berger 2000; Allis et al. 2007; Lee and Workman 2007). These proteins belong to different families, with the best-characterized ones being the GNAT (Gcn5-related N-acetyltransferases) superfamily, the MYST (MOZ, Ybf2/ Sas3, Sas2, and 7ip60) family, the p300 (E1A-associated protein of 300 kDa)/CBP (CREB-binding protein) family, and the fungal-specific Rtt109 (regulator of ty1 transposition 109) family. A comprehensive list of KATs has been compiled and a systematic nomenclature system has been proposed for these enzymes (Allis et al. 2007), but recent additions such as ATAC2 (ADA2A-confaining complex subunit 2) (Suganuma et al. 2008) and MEC17 (mechanosensory abnormal 17) (Akella et al. 2010) will need to be incorporated into the system. p300 and CBP were among the first KATs identified in 1996 (Bannister and Kouzarides 1996; Ogryzko et al. 1996). They do not share any sequence similarity to the GNAT and MYST families, and are conserved from the worm to humans (Goodman and Smolik 2000). Rtt109 is fungi specific and is a structural homolog of p300 and CBP (Tang et al. 2008), suggesting that these KATs can be conceptually grouped into one superfamily.

The GNAT (Gcn5-related N-acetyltransferases) superfamily forms the largest group of KATs (Roth et al. 2001). Family members share several blocks of sequence motifs, one of which is essential for acetyl-CoA binding. Some of the prominent and well-characterized eukaryotic members include HAT1 (histone acetyltransferase 1), GCN5 (general control nonderepressible 5), PCAF (p300/CBP-associated factor, paralog of GCN5), ELP3 (elongation protein 3), CDY (chromodomain on chromsome Y) proteins, Ecol (establishment of cohesion 1), ESCO1 (establishment of cohesion 1 homolog 1), ESCO2 (paralog of ESCO1), ATAC2, and MEC17 (see below). Moreover, this superfamily contains one bacterial KAT called PAT, thereby widening its range from bacteria to humans (Starai and Escalante-Semerena 2004).

Several recent developments about the GNAT family are noteworthy here. First, ATAC2 was identified as a subunit of a multiprotein Gcn5 complex conserved from fly to humans and plays a role in MAP kinase signaling and mitotic progression (Suganuma et al. 2008, 2010; Wang et al. 2008; Guelman et al. 2009; Orpinell et al.

2010). Second, yeast Eco1 and its mammalian orthologs ESCO1 and ESCO2 play key roles in regulating sister chromatid cohesion (Kim and Yang 2011). Third, two recent reports demonstrated that MEC17 proteins from C. elegans and mammals efficiently acetylate a-tubulin at K40 in vitro and in vivo, establishing them as tubulin acetyltransferases (Akella et al. 2010; Shida et al. 2010). Related to this, another report has demonstrated that San acetylates p-tubulin at K252 (Chu et al.

2011). Fourth, in addition to its acetyltransferase domain, ELP3 contains a catalytic domain with a potential role in oxidation, but the function remains to be explored further (Greenwood et al. 2009). Finally, CDY proteins contain a chromodomain and a crotonase-like domain that possesses acetyltransferase activity in vitro (Wu et al. 2009), so it will be interesting to investigate the biological relevance.

The essential acetyl-CoA binding motif conserved in the GNAT superfamily is also present in the MYST family (Lafon et al. 2007). Like the GNAT family, the MYST family has members in all eukaryotes. In humans, there are five members, hMOF (human ortholog of fly mof, MOF, for males absent on the first; also known as MYST1), TIP60 (HIV Tat-interactive protein of 60 kDa), HBO1 (HAT bound to Orc1, also named MYST2), MOZ (monocytic leukemic zinc finger protein, or MYST3), and MORF (MOZ-related factor, or MYST4) (Avvakumov and Cote 2007). Among these, TIP60 is part of a large complex containing over ten proteins, whereas HBO1, MOZ, and MORF are catalytic subunits of tetrameric complexes (Doyon et al. 2006; Avvakumov and Cote 2007; Ullah et al. 2008). Interestingly, subunits of these tetrameric complexes share sequence similarity not only to each other but also to a tetrameric core complex of TIP60 (Avvakumov and Cote 2007). Such similarity is also conserved in yeast MYST proteins (Lafon et al. 2007). By contrast, this similarity is not found in the two complexes containing Mof proteins (Li et al. 2009; Cai et al. 2010; Prestel et al. 2010; Raja et al. 2010), indicating that among members of the MYST family, Mof proteins are different from other members in terms of multisubunit complex formation.

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