Searching distant homologs of the regulatory ACT domain in phenylalanine hydroxylase.
High sequence divergence, evolutionary mobility, and superfold topology characterize the ACT domain. Frequently found in multidomain proteins, these domains induce allosteric effects by binding a regulatory ligand usually to an ACT domain dimer interface. In mammalian phenylalanine hydroxylase (PAH), no contacts are formed between ACT domains, and the domain promotes an allosteric effect despite the apparent lack of ligand binding. The increased functional scenario of this abundant domain encouraged us to search for distant homologs, aiming to enhance the understanding of the ACT domain in general and the ACT domain of PAH in particular. The PDB was searched using the FATCAT server with the ACT domain of PAH as a query. The hits that were confirmed by the SSAP algorithm were divided into known ACT domains (KADs) and potential ACT domains (PADs). The FATCAT/SSAP procedure recognized most of the established KADs, as well 18 so far unrecognized non-redundant PADs with extremely low sequence identities and high divergence in functionality and oligomerization. However, analysis of the structural similarity provides remarkable clustering of the proteins according to similarities in ligand binding. Despite enormous sequence divergence and high functional variability, there is a common regulatory theme among these domains. The results reveal the close relationships of the ACT domain of PAH with amino acid binding and metallobinding ACT domains and with acylphosphatase.
Siltberg-Liberles
Jessica
J
Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
Martinez
Aurora
A
D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D001419:Bacteria / Q000201:enzymology; D001665:Binding Sites; D030562:Databases, Protein; D005658:Fungi / Q000201:enzymology; D051379:Mice; D008969:Molecular Sequence Data; D010651:Phenylalanine Hydroxylase / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D051381:Rats; D016415:Sequence Alignment
D010651:Phenylalanine Hydroxylase