Abstract
Oncostatin M (OSM) and leukemia inhibitory factor are pleiotropic cytokines that belong to the interleukin-6 (IL-6) family. These cytokines play a crucial role in diverse biological events like inflammation, neuroprotection, hematopoiesis, metabolism, and development. The family is grouped together based on structural similarities and their ability to activate the transmembrane receptor glycoprotein 130 (gp130). The common structure among these cytokines defines the spacing and the orientation of binding sites for cell surface receptors. OSM is unique in this family as it can signal using heterodimers of gp130 with either leukemia inhibitory factor receptor (LIFR) (type I) or oncostatin M receptor (OSMR) (type II). We have identified a unique helical loop on OSM between its B and C helices that is not found on other IL-6 family cytokines. This loop is located near the "FXXK" motif in active site III, which is essential for OSM's binding to both LIFR and OSMR. In this study, we show that the BC loop does not play a role in OSM's unique ability to bind OSMR. Shortening of the loop enhanced OSM's interaction with OSMR and LIFR as shown by kinetic and equilibrium binding analysis, suggesting the loop may hinder receptor interactions. As a consequence of improved binding, these structurally modified OSMs exhibited enhanced biological activity, including suppressed proliferation of A375 melanoma cells.
Highlights
Oncostatin M (OSM) has the unique ability to utilize either leukemia inhibitory factor receptor (LIFR) or oncostatin M receptor (OSMR) as a co-receptor
To determine whether the mutant OSMs, OSM-M1 and OSM-M2, still utilize the FXXK motif to interact with LIFR or OSMR, we mutated both Phe-160 and Lys-163 to alanines changing the motif to AXXA. and we evaluated their activity on Muller cells and A375 cells
OSM is unique in terms of its ability to signal through two different receptor complexes, LIFR-gp[130] and OSMR-gp[130]
Summary
OSM has the unique ability to utilize either LIFR or OSMR as a co-receptor. Results: A unique loop in OSM reduces its affinity toward both LIFR and OSMR. Oncostatin M (OSM) and leukemia inhibitory factor are pleiotropic cytokines that belong to the interleukin-6 (IL-6) family. These cytokines play a crucial role in diverse biological events like inflammation, neuroprotection, hematopoiesis, metabolism, and development. OSM is unique in this family as it can signal using heterodimers of gp[130] with either leukemia inhibitory factor receptor (LIFR) (type I) or oncostatin M receptor (OSMR) (type II). We have identified a unique helical loop on OSM between its B and C helices that is not found on other IL-6 family cytokines This loop is located near the “FXXK” motif in active site III, which is essential for OSM’s binding to both LIFR and OSMR. As a consequence of improved binding, these structurally modified OSMs exhibited enhanced biological activity, including suppressed proliferation of A375 melanoma cells
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