The hepatic PP1 glycogen-targeting subunit interaction with phosphorylase a can be blocked by C-terminal tyrosine deletion or an indole drug

TY - JOUR

T1 - The hepatic PP1 glycogen-targeting subunit interaction with phosphorylase a can be blocked by C-terminal tyrosine deletion or an indole drug

AU - Kelsall, Ian R.

AU - Munro, Shonagh

AU - Hallyburton, Irene

AU - Treadway, Judith L.

AU - Cohen, Patricia T. W.

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Animals

KW - Calorimetry

KW - Glycogen Phosphorylase, Liver Form

KW - Humans

KW - Indoles

KW - Mice

KW - Molecular Sequence Data

KW - Mutation

KW - Phenylbutyrates

KW - Protein Binding

KW - Protein Subunits

KW - Rabbits

KW - Rats

KW - Thermodynamics

KW - Titrimetry

KW - Tyrosine

U2 - 10.1016/j.febslet.2007.08.073

DO - 10.1016/j.febslet.2007.08.073

M3 - Article

C2 - 17870073

SN - 0014-5793

VL - 581

SP - 4749

EP - 4753

JO - FEBS Letters

JF - FEBS Letters

IS - 24

ER -