A Unique Loop Structure in Oncostatin M Determines Binding Affinity toward Oncostatin M Receptor and Leukemia Inhibitory Factor Receptor

Chollangi, Srinivas; Mather, Timothy; Rodgers, Karla K.; Ash, John D.

doi:10.1074/jbc.m112.387324

Cited by 19 publications

(24 citation statements)

References 43 publications

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“…Therefore, it was speculated that the extended BC loop might be required for OSM binding to the LIFRb. However, a recent publication showed that shortening the BC loop rather increased the binding affinity of hOSM to the LIFRb as well as to the OSMRb [47]. Plun-Favreau et al [45] could show that mutation of two residues in the N-terminus of the Ig-like domain of the LIFRb (Asp214, Phe284) affected LIF binding much more pronounced than OSM binding, again indicating different binding modes for the two cytokines.…”

Section: Osm Cytokine-receptor Interactionmentioning

confidence: 95%

Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology

Hermanns

2015

Cytokine & Growth Factor Reviews

202

239

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Section: Osm Cytokine-receptor Interactionmentioning

confidence: 95%

Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology

Hermanns

2015

Cytokine & Growth Factor Reviews

202

239

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“…The OSM and LIF residues forming different helices and loops are well known because of the available crystal structures of human OSM (PDB 1EVS) and LIF (PDB 2Q7N) (13,21,25). In contrast, the functional boundaries of OSM binding site III have not been defined precisely.…”

Section: Design and Production Of Osm-lif Chimeric Cytokinesmentioning

confidence: 99%

“…Because no characteristic amino acid demarcating the start of the AB loop was evident, three different replacement lengths were selected. We chose a rather large region comprising the C terminus of helix B and the N terminus of helix C, starting with an Asp and ending with a conserved Lys residue, because shortening of the central region of the BC loop does not impair OSMR activation (21) (Fig. 1D).…”

Section: Design and Production Of Osm-lif Chimeric Cytokinesmentioning

confidence: 99%

“…LIF interacts first with the LIFR before gp130 is recruited and the heteromeric complex forms. In contrast, OSM binds first to gp130 before recruiting the LIFR (3,20,21). After binding to gp130, OSM might alternatively recruit the OSMR to induce OSMR-gp130 complex formation, which is not accomplished by any other cytokine (20).…”

mentioning

confidence: 99%

“…1D) (23). One of the main differences between OSM and LIF is the size of the BC loop, but shortening OSM's longer BC loop does not influence the ability of OSM to bind to the OSMR (21).…”

mentioning

confidence: 99%

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The AB loop and D-helix in binding site III of human Oncostatin M (OSM) are required for OSM receptor activation

Adrian-Segarra

Schindler

Gajawada

et al. 2018

Journal of Biological Chemistry

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Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are closely related members of the interleukin-6 (IL-6) cytokine family. Both cytokines share a common origin and structure, and both interact through a specific region, termed binding site III, to activate a dimeric receptor complex formed by glycoprotein 130 (gp130) and LIF receptor (LIFR) in humans. However, only OSM activates the OSM receptor (OSMR)-gp130 complex. The molecular features that enable OSM to specifically activate the OSMR are currently unknown. To define specific sequence motifs within OSM that are critical for initiating signaling via OSMR, here we generated chimeric OSM-LIF cytokines and performed alanine-scanning experiments. Replacement of the OSM AB loop within OSM's binding site III with that of LIF abrogated OSMR activation, measured as STAT3 phosphorylation at Tyr-705, but did not compromise LIFR activation. Correspondingly, substitution of the AB loop and D-helix in LIF with their OSM counterparts was sufficient for OSMR activation. The alanine-scanning experiments revealed that residues Tyr-34, Gln-38, Gly-39, and Leu-45 (in the AB loop) and Pro-153 (in the D-helix) had specific roles in activating OSMR but not LIFR signaling, whereas Leu-40 and Cys-49 (in the AB loop), and Phe-160 and Lys-163 (in the D-helix) were required for activation of both receptors. Because most of the key amino acid residues identified here are conserved between LIF and OSM, we concluded that comparatively minor differences in a few amino acid residues within binding site III account for the differential biological effects of OSM and LIF.

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Predicting the Long‐Term Effects of Therapeutic Neutralization of Oncostatin M on Human Hematopoiesis

Thorsted,

Zecchin,

Berges

et al. 2024

Clin Pharma and Therapeutics

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Therapeutic neutralization of Oncostatin M (OSM) causes mechanism‐driven anemia and thrombocytopenia, which narrows the therapeutic window complicating the selection of doses (and dosing intervals) that optimize efficacy and safety. We utilized clinical data from studies of an anti‐OSM monoclonal antibody (GSK2330811) in healthy volunteers (n = 49) and systemic sclerosis patients (n = 35), to quantitatively determine the link between OSM and alterations in red blood cell (RBC) and platelet production. Longitudinal changes in hematopoietic variables (including RBCs, reticulocytes, platelets, erythropoietin, and thrombopoietin) were linked in a physiology‐based model, to capture the long‐term effects and variability of therapeutic OSM neutralization on human hematopoiesis. Free serum OSM stimulated precursor cell production through sigmoidal relations, with higher maximum suppression (Imax) and OSM concentration for 50% suppression (IC50) for platelets (89.1% [95% confidence interval: 83.4–93.0], 6.03 pg/mL [4.41–8.26]) than RBCs (57.0% [49.7–64.0], 2.93 pg/mL [2.55–3.36]). Reduction in hemoglobin and platelets increased erythro‐ and thrombopoietin, respectively, prompting reticulocytosis and (partially) alleviating OSM‐restricted hematopoiesis. The physiology‐based model was substantiated by preclinical data and utilized in exploration of once‐weekly or every other week dosing regimens. Predictions revealed an (for the indication) unacceptable occurrence of grade 2 (67% [58–76], 29% [20–38]) and grade 3 (17% [10–25], 3% [0–7]) anemias, with limited thrombocytopenia. Individual extent of RBC precursor modulation was moderately correlated to skin mRNA gene expression changes. The physiological basis and consideration of interplay among hematopoietic variables makes the model generalizable to other drug and nondrug scenarios, with adaptations for patient populations, diseases, and therapeutics that modulate hematopoiesis or exhibit risk of anemia and/or thrombocytopenia.

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A Unique Loop Structure in Oncostatin M Determines Binding Affinity toward Oncostatin M Receptor and Leukemia Inhibitory Factor Receptor

Cited by 19 publications

References 43 publications

Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology

Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology

The AB loop and D-helix in binding site III of human Oncostatin M (OSM) are required for OSM receptor activation

Predicting the Long‐Term Effects of Therapeutic Neutralization of Oncostatin M on Human Hematopoiesis

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