PKU mutation p.G46S prevents the stereospecific binding of l-phenylalanine to the dimer of human phenylalanine hydroxylase regulatory domain
2017
Mammalian
phenylalanine hydroxylase(PAH) has a potential allosteric regulatory binding site for l-
phenylalanine(l-Phe), in addition to its catalytic site. This arrangement is supported by a crystal structure of a homodimeric truncated form of the regulatory domain of human PAH (hPAH-RD1–118/19–118) [Patel D et al. (2016) Sci Rep doi: 10.1038/srep23748]. In this study, a
fusion proteinof the domain (MBP-(pepXa)-hPAH-RD1–120) was overexpressed and recovered in a metastable and soluble state, which allowed the isolation of a dimeric and a monomeric
fusion protein. When
cleavedfrom MBP, hPAH-RD forms aggregates which are stereospecifically inhibited by l-Phe (> 95%) at low physiological concentrations. Aggregation of the
cleaveddimer of the mutant form hPAH-G46S-RD was not inhibited by l-Phe, which is compatible with structurally/conformationally changed βαββαβ
ACT domainfolds in the mutant.
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