PTP catalytic mechanism

the general acid

the general base

WPD loop

D to A mutant

WT (active) PTPs

DA (trapping) PTPs

BackgroundPTP1B Knock Out Mice

PTP1B -/- mice display enhanced sensitivity to insulin

PTP1B -/- mice are resistant to development of obesity and Type 2 diabetes

(Elchebly et al. Science (1999) 83, 1544-1548) (Klaman et al. Mol Cell Biol (2000) 20, 5479-89)

PTP1B -/-PTP1B +/+

Inhibition of the Insulin Receptor PTP may Enhance Insulin Signaling

PTP

Prolonged or Enhanced Signal

Transient Signal

Structure of the PTP1B-IR peptide complex

R1164

pY1163 pY1162

D1161

Arg47

Arg24 Phe182

G1166

Asp48

Arg254

Tyr46

S.R. Hubbard, (1997) EMBO J., 16, 5573-5581

IRTK Activation segment: DIpY1158ETDpY1162pY1163RKGG

Kinetic Constants for Dephosphorylation of IR Activation Loop Peptide by PTP1B

RDIpY1158ETDpY1162pY1163RKGGKGLLIR-peptide

Km

[M]

pY-1158 > 100

pY-1162 > 100

pY-1163 > 100

pY-1162,1163

14 ± 1.1

pY-1158,

1162,1163 7.9 ± 1.3

Insulin

Insulin ReceptorPTK

Signaling Response

PTP1B

PTP1B and insulin signaling

Suppression of PTP1B expression by RNAi may enhance tyrosine phosphorylation of IR

PTP

Prolonged or Enhanced Signal

Transient Signal

972

1158

11621163