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Direct Chemical Activation of a Rationally Engineered Signaling Enzyme
Author(s) -
Chio Cynthia M.,
Cheng Karen W.,
Bishop Anthony C.
Publication year - 2015
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201500245
Subject(s) - enzyme , chemistry , protein tyrosine phosphatase , biochemistry , enzyme activator , cysteine , dephosphorylation , phosphatase , sh2 domain , allosteric regulation , microbiology and biotechnology , biology
Few chemical strategies for activating enzymes have been developed. Here we show that a biarsenical compound (FlAsH) can directly activate a rationally engineered protein tyrosine phosphatase (Shp2 PTP) by disrupting autoinhibitory interactions between Shp2's N‐terminal SH2 domain and its PTP domain. We found that introducing a tricysteine motif at a loop of Shp2's N‐SH2 domain confers affinity for FlAsH; binding of FlAsH to the cysteine‐enriched loop relieves Shp2's inhibitory interdomain interaction and substantially increases the enzyme's PTP activity. Activation of engineered Shp2 is substrate independent and is observed in the contexts of both purified enzyme and complex proteomes. A chemical means for activating Shp2 could be useful for investigating its roles in signaling and oncogenesis, and the loop‐targeting strategy described herein could provide a blueprint for the development of target‐specific activators of other autoinhibited enzymes.