The ACT domain: A small molecule binding domain and its role as a common regulatory element

ACT domains are found in a wide variety of proteins and in a variety of different arrangements. The majority of these bind amino acids that function to regulate some aspect of amino acid metabolism. Most ACT domain-containing proteins have been discovered in Bacteria and Archaea, indicating that the domain appeared very early on. At least one functional example has been found in a mammalian protein, rat phenylalanine hydroxylase. Interestingly, ACT domains are not found in all organisms nor are they used consistently within species or found in all proteins possessing a common activity. In their original article, Aravind and Koonin (2) suggested that the ACT domain represents a "conserved, evolutionarily mobile module" that when fused to other proteins made them susceptible to regulation by small molecules. The large variety of ACT domain-containing proteins is consistent with this idea, but they do not appear to be used universally within a single species. The preponderance of ACT domains that bind amino acids suggests that this was its original function. However, there are obvious examples that it is evolving to bind other ligands and perhaps participate in the regulation of other processes. One should anticipate that the realm of the ACT domain as a regulatory element will continue to expand as more structures are determined and more is learned about their respective functions. What was once just a very short story is developing into a drama with many ACTs.