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Title: Topological control of cytokine receptor signaling induces differential effects in hematopoiesis

Abstract

Although tunable signaling by G protein–coupled receptors can be exploited through medicinal chemistry, a comparable pharmacological approach has been lacking for the modulation of signaling through dimeric receptors, such as those for cytokines. We present a strategy to modulate cytokine receptor signaling output by use of a series of designed C2-symmetric cytokine mimetics, based on the designed ankyrin repeat protein (DARPin) scaffold, that can systematically control erythropoietin receptor (EpoR) dimerization orientation and distance between monomers. We sampled a range of EpoR geometries by varying intermonomer angle and distance, corroborated by several ligand-EpoR complex crystal structures. Across the range, we observed full, partial, and biased agonism as well as stage-selective effects on hematopoiesis. Lastly, this surrogate ligand strategy opens access to pharmacological modulation of therapeutically important cytokine and growth factor receptor systems.

Authors:
ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [3]; ORCiD logo [4]; ORCiD logo [2]; ORCiD logo [5]; ORCiD logo [6]; ORCiD logo [1]; ORCiD logo [7]; ORCiD logo [8]; ORCiD logo [3]; ORCiD logo [9]; ORCiD logo [10]
  1. Stanford Univ., CA (United States). School of Medicine
  2. Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry, and Inst. for Protein Design
  3. Boston Children’s Hospital and Harvard Medical School, Boston, MA (United States). Division of Hematology/Oncology, The Manton Center for Orphan Disease Research; Harvard Medical School, Boston, MA (United States). Dana-Farber Cancer Inst., Dept. of Pediatric Oncology; Broad Inst. of MIT and Harvard, Cambridge, MA (United States)
  4. Stanford Univ., CA (United States). Howard Hughes Medical Inst.
  5. Nankai Univ., Tianjin (China). State Key Lab. of Medicinal Chemical Biology and College of Pharmacy
  6. Univ. of Osnabrück, Osnabrück (Germany). Division of Biophysics, Dept. of Biology
  7. Stanford Univ., CA (United States). School of Medicine, and Howard Hughes Medical Inst.
  8. Univ. of Osnabrück, Osnabrück (Germany). Division of Biophysics, Dept. of Biology, and Center for Cellular Nanoanalytics
  9. Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry, and Inst. for Protein Design, and Howard Hughes Medical Inst.
  10. Stanford Univ., CA (United States). School of Medicine, Howard Hughes Medical Inst., and Dept. of Structural Biology
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH); German Research Foundation (DFG)
OSTI Identifier:
1532487
Grant/Contract Number:  
AC02-76SF00515; AC02-06CH11357; AC02-05CH11231; S10OD021832; R01-AI51321; T32HL066987; R01 DK103794; R33 HL120791; 1S10OD012289-01A1
Resource Type:
Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 364; Journal Issue: 6442; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Mohan, Kritika, Ueda, George, Kim, Ah Ram, Jude, Kevin M., Fallas, Jorge A., Guo, Yu, Hafer, Maximillian, Miao, Yi, Saxton, Robert A., Piehler, Jacob, Sankaran, Vijay G., Baker, David, and Garcia, K. Christopher. Topological control of cytokine receptor signaling induces differential effects in hematopoiesis. United States: N. p., 2019. Web. doi:10.1126/science.aav7532.
Mohan, Kritika, Ueda, George, Kim, Ah Ram, Jude, Kevin M., Fallas, Jorge A., Guo, Yu, Hafer, Maximillian, Miao, Yi, Saxton, Robert A., Piehler, Jacob, Sankaran, Vijay G., Baker, David, & Garcia, K. Christopher. Topological control of cytokine receptor signaling induces differential effects in hematopoiesis. United States. https://doi.org/10.1126/science.aav7532
Mohan, Kritika, Ueda, George, Kim, Ah Ram, Jude, Kevin M., Fallas, Jorge A., Guo, Yu, Hafer, Maximillian, Miao, Yi, Saxton, Robert A., Piehler, Jacob, Sankaran, Vijay G., Baker, David, and Garcia, K. Christopher. Thu . "Topological control of cytokine receptor signaling induces differential effects in hematopoiesis". United States. https://doi.org/10.1126/science.aav7532. https://www.osti.gov/servlets/purl/1532487.
@article{osti_1532487,
title = {Topological control of cytokine receptor signaling induces differential effects in hematopoiesis},
author = {Mohan, Kritika and Ueda, George and Kim, Ah Ram and Jude, Kevin M. and Fallas, Jorge A. and Guo, Yu and Hafer, Maximillian and Miao, Yi and Saxton, Robert A. and Piehler, Jacob and Sankaran, Vijay G. and Baker, David and Garcia, K. Christopher},
abstractNote = {Although tunable signaling by G protein–coupled receptors can be exploited through medicinal chemistry, a comparable pharmacological approach has been lacking for the modulation of signaling through dimeric receptors, such as those for cytokines. We present a strategy to modulate cytokine receptor signaling output by use of a series of designed C2-symmetric cytokine mimetics, based on the designed ankyrin repeat protein (DARPin) scaffold, that can systematically control erythropoietin receptor (EpoR) dimerization orientation and distance between monomers. We sampled a range of EpoR geometries by varying intermonomer angle and distance, corroborated by several ligand-EpoR complex crystal structures. Across the range, we observed full, partial, and biased agonism as well as stage-selective effects on hematopoiesis. Lastly, this surrogate ligand strategy opens access to pharmacological modulation of therapeutically important cytokine and growth factor receptor systems.},
doi = {10.1126/science.aav7532},
journal = {Science},
number = 6442,
volume = 364,
place = {United States},
year = {2019},
month = {5}
}

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Works referencing / citing this record:

Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations
text, January 2019


Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations
journal, February 2020