Bromodomains PHD Fingers and Potentially Others for AcK Recognition

Acetylation affects protein function through various mechanisms, with one of them being recognition by protein domains such as the bromodomain. It has been well established that the bromodomain of GCN5, TAF250, or p300 forms an a-helix bundle containing a specific pocket for recognition of a specific AcK residue (Sanchez and Zhou 2009). The binding affinity is relatively weak but provides an opportunity to cooperate with other protein modules. For example, TRIM24 (tripartite motif-containing 24, also known as TIF1a) possesses a bromodomain adjacent to a PHD finger for combinatorial recognition of histone marks (Tsai et al. 2010). While its PHD finger binds to the unmodified N-terminal tail of histone H3, its bromodomain recognizes AcK23 of histone H3, with acetylation increasing the affinity by about 23-fold and the Kd value dropping from 2.3 to 0.1 p.M. TRIM24 is a biomarker whose overexpression is associated with breast cancer. In addition to the classical one-to-one interaction mode, a recent study has shown that one bromodomain of BRDT (bromodomain-containing testis specific) recognizes his-tone H4 diacetylated at K5 and K8 (Moriniere et al. 2009), indicating that one bromodomain can recognize two AcK residues. In addition to bromodomains, PHD fingers also possess the ability of AcK recognition. DPF3b (D4, zinc and double PHD fingers, family 3b) contains tandem PHD fingers (Zeng et al. 2010). The second PHD finger interacts an unmodified histone H3 tail through R2, K4, and K9, whereas the first finger forms a binding pocket for AcK14 and stimulates the affinity for histone H3 by threefold.

The bromodomain and PHD finger proteins are mainly nuclear, so an interesting issue is whether AcK-binding domains are also present in the cytoplasm. This possibility has been raised by others (Norris et al. 2009) and will be a new and potentially exciting avenue for further research.

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