title: Essential role of the N-terminal autoregulatory sequence in the regulation of phenylalanine hydroxylase.
abstract: Phenylalanine hydroxylase (PAH) is activated by its substrate phenylalanine and inhibited by its cofactor tetrahydrobiopterin (BH(4)). The crystal structure of PAH revealed that the N-terminal sequence of the enzyme (residues 19-29) partially covered the enzyme active site, and suggested its involvement in regulation. We show that the protein lacking this N-terminal sequence does not require activation by phenylalanine, shows an altered structural response to phenylalanine, and is not inhibited by BH(4). Our data support the model where the N-terminal sequence of PAH acts as an intrasteric autoregulatory sequence, responsible for transmitting the effect of phenylalanine activation to the active site.
authors.affiliation: Structural Biology Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Vic., Australia.
authors.forename: I G
authors.initials: IG
authors.lastname: Jennings
authors.forename: T
authors.initials: T
authors.lastname: Teh
authors.forename: B
authors.initials: B
authors.lastname: Kobe
mesh_terms: D001665:Binding Sites; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002918:Chymotrypsin / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D008958:Models, Molecular; D010649:Phenylalanine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D010651:Phenylalanine Hydroxylase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D011994:Recombinant Proteins; D001708:Biopterins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; D002918:Chymotrypsin; C003402:sapropterin