A Protein Phosphorylation Switch at the Conserved Allosteric Site in GP

• Published in: Science (American Association for the Advancement of Science) 1996-09, Vol.273 (5281), p.1539-1541
• Main Authors: Lin, Kai, Rath, Virginia L., Dai, Shirleko C., Fletterick, Robert J., Hwang, Peter K.
• Format: Article
• Language: English
• Subjects: Active sites; Adenosine Monophosphate - metabolism; Allosteric Site; Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Animals; Biochemistry; Biological and medical sciences; Biophysics; Cell regulation; Cellular control mechanisms; Crystallography, X-Ray; Dimers; Enzyme Activation; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Enzymes; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Glucose-6-Phosphate; Glucosephosphates - metabolism; Glucosephosphates - pharmacology; Glycogen; Group facilitation; Models, Molecular; Molecular Sequence Data; Phosphatases; Phosphates; Phosphorylases - antagonists & inhibitors; Phosphorylases - chemistry; Phosphorylases - metabolism; Phosphorylation; Physics; Physiological aspects; Protein Conformation; Protein Folding; Protein Structure, Secondary; Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae - enzymology; Transferases; Yeasts
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.273.5281.1539

A phosphorylation-initiated mechanism of local protein refolding activates yeast glycogen phosphorylase (GP). Refolding of the phosphorylated amino-terminus was shown to create a hydrophobic cluster that wedges into the subunit interface of the enzyme to trigger activation. The phosphorylated threonine is buried in the allosteric site. The mechanism implicates glucose 6-phosphate, the allosteric inhibitor, in facilitating dephosphorylation by dislodging the buried covalent phosphate through binding competition. Thus, protein phosphorylation-dephosphorylation may also be controlled through regulation of the accessibility of the phosphorylation site to kinases and phosphatases. In mammalian glycogen phosphorylase, phosphorylation occurs at a distinct locus. The corresponding allosteric site binds a ligand activator, adenosine monophosphate, which triggers activation by a mechanism analogous to that of phosphorylation in the yeast enzyme.