Evolutionarily Conserved Allosteric Communication in Protein Tyrosine Phosphatases

Protein
tyrosine phosphatases (PTPs) are an important class of
regulatory enzymes that exhibit aberrant activities in a wide range
of diseases. A detailed mapping of allosteric communication in these
enzymes could, thus, reveal the structural basis of physiologically
relevantand, perhaps, therapeutically informativeperturbations
(i.e., mutations, post-translational modifications, or binding events)
that influence their catalytic states. This study combines detailed
biophysical studies of protein tyrosine phosphatase 1B (PTP1B) with
bioinformatic analyses of the PTP family to examine allosteric communication
in this class of enzymes. Results of X-ray crystallography, molecular dynamics simulations,
and sequence-based statistical analyses indicate that PTP1B possesses
a broadly distributed allosteric network that is evolutionarily conserved
across the PTP family, and findings from both kinetic studies and mutational
analyses show that this network is functionally intact in sequence-diverse
PTPs. The allosteric network resolved in this study reveals new sites
for targeting allosteric inhibitors of PTPs and helps explain the
functional influence of a diverse set of disease-associated mutations.