Differentialfunctionsof the two Src homology2 protein tyrosinephosphatase SH-PTP1 domains in
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SH-PTP1 (also knownas PTP1C, HCP, and SHP) is a non-transmembranperoteintyrosinephosphatase (PTPase) containing two tandem Src homology2 (SH2) domains.We showherethatthetwoSH2 (N-SH2 and C-SH2) domainsin SH-PTP1 havedifferenftunctionsin regulationof the PTPase domain and therebysignal transduction.While the N-terminalSH2 domainis bothnecessaryand sufficient forautoinhibitionthroughan intramolecularassociationwith the PTPase domain,truncationof the C-SH2 domain [SH- PTP1(ACSH2) construct]has littleeffecton SH-PTP1 activ- ity.A synthetipchosphotyrosinreesidue(pY) peptidederived fromthe erythropoietinreceptor(EpoR pY429) binds to the N-SH2 domain and activatesboth wild-typeSH-PTP1 and SH-PTP1(ACSH2) 60- to 80-fold.AnotherpY peptidecorre- spondingto a phosphorylationsite on the IgG Fc receptor (FcyRIIB1 pY309) associateswithboththeC-SH2 domain(Kd = 2.8 ,uM) and theN-SH2 domain (Kd = 15.0 ,uM) and also activatesSH-PTP1 12-fold.By analysis of the effectof the FcyRIIB1 pY309 peptide on SH-PTP1(ACSH2), SH- PTP1(R30K/R33E), SH-PTPI(R30K/R136K), and SH- PTPI(R136K) mutantsin whichthefunctionofeithertheN- or C-SH2 domainhas beenimpaired,wehavedeterminedthat bothsyntheticpY peptidesstimulateSH-PTP1 bybindingto itsN-SH2 domain;bindingofpY ligandto theC-SH2 domain has no effecton SH-PTP1 activity.We propose that the N-terminalSH2 domain servesbothas a regulatorydomain and as a recruitingunit,whereastheC-terminalSH2 domain acts merelyas a recruitingunit.
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