Nature Structural Biology
6, 442 - 448 (1999)
doi:10.1038/8247
Structural basis of autoregulation of phenylalanine hydroxylaseBostjan Kobe1, Ian G. Jennings1, 2, Colin M. House1, 3, Belinda J. Michell1, Kenneth E. Goodwill4, Bernard D. Santarsiero4, Raymond C. Stevens4, Richard G. H. Cotton2
& Bruce E. Kemp11
St. Vincent's Institute of Medical Research,
41 Victoria Parade, Fitzroy, Victoria 3065
, Australia
2
Mutation Research Center, 41 Victoria
Parade, Fitzroy, Victoria 3065,
Australia
3
Present address: Trescowthick Research Laboratories,
Peter MacCallum Cancer Institute, Locked Bag No 1, A'Beckett
St., Melbourne 3000, Australia
4
Department of Chemistry and Earnest Orlando Lawrence
Berkeley National Laboratory, University of California, Berkeley
, California 94720, USA
Correspondence should be addressed to Bostjan Kobe B.Kobe@medicine.unimelb.edu.auPhenylalanine hydroxylase converts phenylalanine to tyrosine, a rate-limiting
step in phenylalanine catabolism and protein and neurotransmitter biosynthesis.
It is tightly regulated by the substrates phenylalanine and tetrahydrobiopterin
and by phosphorylation. We present the crystal structures of dephosphorylated
and phosphorylated forms of a dimeric enzyme with catalytic and regulatory
properties of the wild-type protein. The structures reveal a catalytic domain
flexibly linked to a regulatory domain. The latter consists of an N-terminal
autoregulatory sequence (containing Ser 16, which is the site of phosphorylation)
that extends over the active site pocket, and an  - sandwich core
that is, unexpectedly, structurally related to both pterin dehydratase and
the regulatory domains of metabolic enzymes. Phosphorylation has no major
structural effects in the absence of phenylalanine, suggesting that phenylalanine
and phosphorylation act in concert to activate the enzyme through a combination
of intrasteric and possibly allosteric mechanisms.
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