title: A unique loop structure in oncostatin M determines binding affinity toward oncostatin M receptor and leukemia inhibitory factor receptor.
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.
authors: Department of Bioengineering, University of Oklahoma, Norman, Oklahoma 73019, USA.
authors: Srinivas
authors: S
authors: Chollangi
authors: Timothy
authors: T
authors: Mather
authors: Karla K
authors: KK
authors: Rodgers
authors: John D
authors: JD
authors: Ash
mesh_terms: D020816:Amino Acid Motifs; D045744:Cell Line, Tumor; D006801:Humans; D007700:Kinetics; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D053683:Oncostatin M / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D053681:Oncostatin M Receptor beta Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C508348:OSMR protein, human; D053681:Oncostatin M Receptor beta Subunit; D053683:Oncostatin M