STATs (Signal transducers and activators of transcription) were named by virtue of their dual functions as signaling molecules in the cytoplasm and as transcription factors after nuclear translocation, which are comprised of seven members in mammalian cells namely, Stat1, Stat2, Stat3, Stat4, Stat5a, Stat5b, and Stat6. Among them, Stat3 has received a lot of attention because of its important roles in the proliferation, survival, and invasion of cancer cell by promoting pro-oncogenic inflammation and suppressing anti-tumor immunity.<br/>STAT3 signaling pathway involves multiple distinct steps: cell-surface receptors once upon activation will recruit their associated kinases that will phosphorylate the tail of receptors on a tyrosine site, which will provide a binding site for STAT3 being recruited to the cell-surface receptors. Once binding to the receptors, receptors associated kinases will activate STAT3 through phosphorylating a specific tyrosine within the C terminus (Tyr705), and the phosphorylated STAT3 monomers dissociate from the receptor to form STAT3-STAT3 homodimers translocate to the nucleus and bind to specific promoter sequences on their target genes, promoting the expression of proteins crucial for cell growth and survival.<br/>In a normal cell, the signaling pathway is well regulated. However, the abnormal activation of this signaling pathway will promote the development of cancer. The direct therapeutic inhibition of STAT3 is highly desirable but remains challenging as evident from the lack of FDA-approved drugs. For a long time, SH2 domain has been the target, however, recent studies surprisingly found the effector binding to CCD will inhibit SH2 domain binding to receptors, further preclude STAT3 dimerization. But how CCD crosstalk with SH2 mediating the SH2 domain binding with receptors? We aim to use simulation to investigate the protein dynamics to get insights about 1. SH2 domain configuration change with/without effectors binding (effectors: small molecules binding to CCD); 2. analyze dynamics to identify allosteric network of residues required for CCD crosstalk with SH2.

Crosstalk between SH2 and CCD of STAT3

ACS Fall 2021

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