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The ACT Domain: A Small Molecule Binding Domain and Its Role as a Common Regulatory Element*

G. A. Grant

Published 2006 in Journal of Biological Chemistry

ABSTRACT

The ACT domain is a structural motif in proteins of 70–80 amino acids that is one of a growing number of different intracellular small molecule binding domains that function in the control of metabolism, solute transport, and signal transduction (1–5). The first structure of an ACT domain was determined in 1995 with the crystal structure of Escherichia coli D-3phosphoglycerate dehydrogenase (6), a tetrameric protein containing one ACT domain per subunit. This structure represents the archetypical ACT domain and is composed of four strands and two helices arranged in a fold as shown in Fig. 1. However, it was not recognized as a recurring motif until 1999whenAravind andKoonin (2) proposed this based on a PSI-Blast (position-specific iterating-Blast) sequence data base search using the small subunit (IlvN) of acetolactate synthase. This search identified a diverse group of proteins that were noted to be involved in someway in amino acid and purine metabolism and were regulated by specific amino acids. They named this proposed domain the ACT domain after the first letters of three of the proteins, aspartate kinase-chorismate mutase-tyrA (prephenate dehydrogenase). In 2001, the structure of the Lrp-like transcriptional regulator fromPyrococcus furiosiswas published (7). This was the first structure of a transcription factor that contained an ACT domain. A PSI-Blast analysis of its sequence by Ettema et al. (3) revealed an additional group of proteins, including both enzymes and transcription regulators, that they proposed contained a novel type of ACT domain, which they named the RAMdomain for regulator of amino acidmetabolism. The Lrplike transcriptional regulator contains the ACT domain fold ( ), but the sequence alignment resulting from the PSIBlast search appeared to reveal a somewhat different pattern of conservation of residue type (3) (Fig. 2). Mutagenesis data also suggested that the ligand binding sites of the Lrp-like protein were located differently than in the ACT domains described previously. Although the ACT domain from E. coli D-3-phosphoglycerate dehydrogenase and the Lrp-like transcription factor superimpose very well (1.8-Å root mean square deviation), the dimer interfaces of each are significantly different. The ACT domain dimers of phosphoglycerate dehydrogenase form a side-by-side structure producing an extended 8-stranded sheet (Fig. 3A). On the other hand, the sheets of the ACT domain dimers of the Lrp transcription factor assume a more face-to-face configuration (Fig. 3J). These observations formed the basis for the proposed division into ACT and RAM domains. As will be seen later in this review, recently determined structures demonstrate that the ACT domain shows an increasing diversity in tertiary and quaternary architecture as well as ligand binding interactions. A novel type of ACT domain-containing protein family whose members contain ACT domain repeats has also been identified by sequence analysis in Arabadopsis (8). These proteins were termed ACR proteins. There are at least 8 genes in the 5 chromosomes of Arabadopsis that belong to the “ACR” protein family. Proteins similar to the ACR family have also been identified in rice (Oryza sativa) (9). The majority of ACT domain-containing proteins appear to interact with amino acids and are involved in some aspect of regulation of amino acid metabolism (2–4) (Fig. 1). These include both metabolic enzymes and transcription regulators. In fact, the expression of some ACT-containing enzymes is under the control of ACT-containing transcription regulators. This has resulted in the ACT domain being referred to as “the regulatory domain in amino acid metabolism” in the SCOP (structural classification of proteins) data base. However, notable exceptions to this generality have been revealed in recent years. These include the NikR transcriptional regulator that binds nickel and functions in the regulation of intracellular nickel levels (10) and the YkoF protein (11) that binds thiamine and is thought to be involved in thiamine transport. It is noteworthy that the 80–90-amino acid long ribonucleoprotein motif of RNA binding proteins (12, 13) also possesses the same fold as the ACT domain. These domains bind RNA through interaction at the face of their -sheet structure rather than binding smallmolecules in loop regions like the ACT domains. It is not known how these very similar domains may be related evolutionarily, but their similarity is intriguing. The RNA binding domains have their own unique pattern of conserved consensus sequences and the PSI-Blast searches that identified the ACT and RAM domains did not appear to select any RNA binding domains.

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