Evolutionarily Conserved Allosteric Communication in Protein Tyrosine Phosphatases

Abstract

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 PTPs. 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 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. File list (2) download file view on ChemRxiv Manuscript Revised.pdf (12.05 MiB) download file view on ChemRxiv Supporting Information Revised.pdf (17.02 MiB)

Study on a Fermented Whole Wheat: Phenolic Content, Activity on PTP1B Enzyme and In Vitro Prebiotic Properties

“…In light with these findings, we can conclude that Lisosan ® G contains unknown molecules that impede the interaction with the enzyme. These results agrees with recent evidence that confirmed the presence of different allosteric sites on the enzyme surface involved in the regulation of the enzyme activity [21]. Furthermore, it was possible to affirm that the cinnamic components alone were not responsible for such higher inhibitory activity; in fact from literature, ferulic acid in high concentration (100 μM) only exerted a weak inhibition (15%) on PTP1B [22].…”

Crystal Structure of TCPTP Unravels an Allosteric Regulatory Role of Helix α7 in Phosphatase Activity

“…After examining the role of helix α7 in regulation of TCPTP’s catalytic activity, we wondered whether helix α7 also exists in other members of the PTP superfamily. Earlier studies had suggested that the helix-α7-mediated regulation might be specific for PTP1B. , Furthermore, a recent work had highlighted that helix α7 modulates the conserved allosteric network to influence the activity of PTPs . To explore this, we superimposed all available crystal structures from nonreceptor PTPs (Figure A) and D1 domains of receptor-type PTPs (Figure B).…”

“…Among all structures being solved, none of them except for PTP1B and TCPTP have revealed helix α7 (Figure A,B). However, it should be noted that, although helix α7 is absent from the C-terminal region of these PTP structures, allosteric regulation may be executed by other helical segments or domains from the C-terminal region if they are capable of forming intramolecular interactions with the allosteric site in the PTP domain as the network is conserved across the family . Indeed, many nonreceptor PTPs contain a large C-terminal region that has not been fully characterized in detail but may function as an allosteric regulator.…”

Unraveling the Allosteric Cross-Talk Between Coactivator Peptide and Ligand Binding Site in Glucocorticoid Receptor

“…To further support this hypothesis, a bioinformatic analysis was conducted to assess the evolutionarily conservation and co-evolution of the critical nodes within the 3-ketosteroid nuclear receptor (NR3C) family. Indeed, both evolutionarily conserved and co-evolving residues are known to maintain the structural integrity and to regulate the function of the proteins 29,30,31,32,33 and they might coincide with the critical nodes identified in the MD-generated network analysis. Figure S2A shows an high conservation of the residues forming the 'route 2'.…”