A new model for allosteric regulation of phenylalanine hydroxylase: implications for disease and therapeutics.

ABSTRACT: The structural basis for allosteric regulation of phenylalanine hydroxylase (PAH), whose dysfunction causes phenylketonuria (PKU), is poorly understood. A new morpheein model for PAH allostery is proposed to consist of a dissociative equilibrium between two architecturally different tetramers whose interconversion requires a ∼90° rotation between the PAH catalytic and regulatory domains, the latter of which contains an ACT domain. This unprecedented model is supported by in vitro data on purified full length rat and human PAH. The conformational change is both predicted to and shown to render the tetramers chromatographically separable using ion exchange methods. One novel aspect of the activated tetramer model is an allosteric phenylalanine binding site at the intersubunit interface of AC

SUBMITTER: Jaffe EK 

PROVIDER: S-EPMC3580015 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature