Structural basis of autoregulation of phenylalanine hydroxylase

摘要: Phenylalanine hydroxylase converts phenylalanine to tyrosine, a rate-limiting step in catabolism and protein neurotransmitter biosynthesis. It is tightly regulated by the substrates tetrahydrobiopterin phosphorylation. We present crystal structures of dephosphorylated phosphorylated forms dimeric enzyme with catalytic regulatory properties wild-type protein. The reveal domain flexibly linked domain. latter consists an N-terminal autoregulatory sequence (containing Ser 16, which site phosphorylation) that extends over active pocket, alpha-beta sandwich core is, unexpectedly, structurally related both pterin dehydratase domains metabolic enzymes. Phosphorylation has no major structural effects absence phenylalanine, suggesting phosphorylation act concert activate through combination intrasteric possibly allosteric mechanisms.