Searching distant homologs of the regulatory ACT domain in phenylalanine hydroxylase |
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Authors: | Jessica Siltberg-Liberles Aurora Martinez |
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Institution: | (1) Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway;(2) Department of Molecular Biology, University of Wyoming, Laramie, WY 82071, USA; |
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Abstract: | 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. |
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