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Abstract
The immunomodulatory effects of Suppressor of Cytokine Signaling (SOCS) proteins, that control the JAK/STAT pathway, indicate them as attractive candidates for immunotherapies. Recombinant SOCS3 protein suppresses the effects of inflammation, and its deletion in neurons or in immune cells increases pathological blood vessels growth. Recently, on the basis of the structure of the ternary complex among SOCS3, JAK2, and gp130, we focused on SOCS3 interfacing regions and designed several interfering peptides (IPs) that were able to mimic SOCS3 biological role in triple negative breast cancer (TNBC) models. Herein, to explore other protein regions involved in JAK2 recognition, several new chimeric peptides connecting noncontiguous SOCS3 regions and including a strongly aromatic fragment were investigated. Their ability to recognize the catalytic domain of JAK2 was evaluated through MST (microscale thermophoresis), and the most promising compound, named KIRCONG chim, exhibited a low micromolar value for dissociation constant. The conformational features of chimeric peptides were analyzed through circular dichroism and NMR spectroscopies, and their anti-inflammatory effects were assessed in cell cultures. Overall data suggest the importance of aromatic contribution in the recognition of JAK2 and that SOCS3 peptidomimetics could be endowed with a therapeutic potential in diseases with activated inflammatory cytokines.
Highlights
The immunomodulatory effects of Suppressor of Cytokine Signaling (SOCS) proteins, that control the JAK/STAT pathway, indicate them as attractive candidates for immunotherapies
SOCS3 acquired from alveolar macrophage-derived extracellular vesicles restrains epithelial tumorigenesis, while its deficiency at the mucosal surface contributes to epithelial cell transformation and allows growth and survival of mature tumor cells.[13]
JAK2/gp[130] indicates that other contacts involving some residues in a “hinge” region between ESS and helix A (HA) of the SOCS3-SH2 domain are crucial for the formation of the complex
Summary
SOCS3/JAK2 kinase domain/gp[130] phosphotyrosine-peptide was employed to design mimetics of SOCS3.34 From its inspection, SOCS3 appeared to interact with JAK2 and gp[130] simultaneously through adjacent interfaces: KIR and ESS domains appeared mainly involved in the recognition of “GQM” and helix G motifs of JAK2 essentially through hydrophobic interactions. Spectra in buffer present one minimum around 200 nm indicating a prevalent random content even if the presence of a shoulder at ∼215 nm suggests a small contribution of helical conformations and, in the case of KIRCONG chim, a positive slight band at ∼235 nm suggests a direct involvement of aromatic residues in the conformational features of the sequence.[38] To evaluate the effects of TFE addition on the conformational features of designed sequences, we followed the variation of Θratio value at increasing concentration of the cosolvent, as reported as insets of Figure 1, lower panels. The greater stability shown by KIRCONG chim is likely due to the presence of three β-alanines as “non native” amino acid Overall data indicated antiinflammatory and antioxidant effects of SOCS3 peptides and support further investigations of their potential in inflammatory diseases, including atherosclerosis
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