Kelsall Ian R, Munro Shonagh, Hallyburton Irene, Treadway Judith L, Cohen Patricia T W
Medical Research Council, Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
FEBS Lett. 2007 Oct 2;581(24):4749-53. doi: 10.1016/j.febslet.2007.08.073. Epub 2007 Sep 6.
The inhibition of hepatic glycogen-associated protein phosphatase-1 (PP1-G(L)) by glycogen phosphorylase a prevents the dephosphorylation and activation of glycogen synthase, suppressing glycogen synthesis when glycogenolysis is activated. Here, we show that a peptide ((280)LGPYY(284)) comprising the last five amino acids of G(L) retains high-affinity interaction with phosphorylase a and that the two tyrosines play crucial roles. Tyr284 deletion abolishes binding of phosphorylase a to G(L) and replacement by phenylalanine is insufficient to restore high-affinity binding. We show that a phosphorylase inhibitor blocks the interaction of phosphorylase a with the G(L) C-terminus, suggesting that the latter interaction could be targeted to develop an anti-diabetic drug.
糖原磷酸化酶a对肝糖原相关蛋白磷酸酶-1（PP1-G(L)）的抑制作用可防止糖原合酶的去磷酸化和激活，在糖原分解被激活时抑制糖原合成。在此，我们表明，包含G(L)最后五个氨基酸的肽（(280)LGPYY(284)）与磷酸化酶a保持高亲和力相互作用，且两个酪氨酸发挥着关键作用。Tyr284缺失消除了磷酸化酶a与G(L)的结合，用苯丙氨酸替代不足以恢复高亲和力结合。我们表明，一种磷酸化酶抑制剂可阻断磷酸化酶a与G(L) C末端的相互作用，这表明后一种相互作用可能是开发抗糖尿病药物的靶点。
