Title: “Unravelling the information processing patterns of SH2 domains participating in the JAK/STAT signaling pathway”
- Machine Learning Group, Computer Science Department, ULB
- Signal transduction group, Structure and function of cytokine receptors, Ludwig Institute for Cancer Research, UCL
This project aims to provide the structural basis for the different allosteric properties of several SH2 domains, which participate in the common JAK-STAT signaling pathway. On a broad level, we aim to grasp the functional relevance, evolutionary importance and the effect of artificial or disease-related mutations in this class of SH2-containing proteins. To achieve these general goals, we focus here on the three SH2 domains belonging to the proteins SOCS3 and SHP2, which are both implicated in the attenuation of the JAK/STAT pathway. After the in silico identification of those residues implicated in the long-range communication through the SH2 structures, these dynamics will be validated using NMR relaxation experiments and functional assays in living cells. The residues implicated in signal transmission are expected to correspond to a particular sequence pattern, whose conservation within the family of SH2 domains will be evaluated. These new insights will provide a novel perspective on the existing classifications of this family and, in addition, a validation of alternative methods to multiple sequence alignments to predict the allosteric patterns within that family. Finally, the knowledge derived from the previous steps will be used to design an algorithm to create artificial members of the SH2 family with communication patterns similar to the one(s) previously analyzed. These artificial versions will be examined for folding and binding and their dynamics will be compared with their natural counterparts using NMR. Once they behave correctly, chimeras of the SOCS3 and SHP2 proteins will be tested within living cells. Overall, we aim not only to provide insight into the allosteric nature of SH2 domains, but also to decipher the intimate mechanism of SOCS3 and SHP2 function in modulation of JAK/STAT signaling.