The hepatic PP1 glycogen-targeting subunit interaction with phosphorylase a can be blocked by C-terminal tyrosine deletion or an indole drug.
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.
Kelsall
Ian R
IR
Medical Research Council, Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Munro
Shonagh
S
Hallyburton
Irene
I
Treadway
Judith L
JL
Cohen
Patricia T W
PT
D000595:Amino Acid Sequence; D000818:Animals; D002151:Calorimetry; D025001:Glycogen Phosphorylase, Liver Form / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010654:Phenylbutyrates / Q000494:pharmacology*; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013816:Thermodynamics; D017186:Titrimetry; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*
C504712:3-(5-chloroindole-2-carbonyl)amino-2-hydroxy-4-phenylbutyric acid N-methyl-N-methoxyamide; D007211:Indoles; D010654:Phenylbutyrates; D021122:Protein Subunits; D014443:Tyrosine; D025001:Glycogen Phosphorylase, Liver Form