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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. 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, and Garcia, K. Christopher. Thu . "Topological control of cytokine receptor signaling induces differential effects in hematopoiesis". United States. doi: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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Cited by: 8 works
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    Works referencing / citing this record:

    Selecting Agonists from Single Cells Infected with Combinatorial Antibody Libraries
    journal, May 2013


    Apoptotic mechanisms in the control of erythropoiesis
    journal, June 2004


    PHENIX: a comprehensive Python-based system for macromolecular structure solution
    journal, January 2010

    • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
    • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
    • DOI: 10.1107/s0907444909052925

    Automated refinement of macromolecular structures at low resolution using prior information
    journal, September 2016

    • Kovalevskiy, Oleg; Nicholls, Robert A.; Murshudov, Garib N.
    • Acta Crystallographica Section D Structural Biology, Vol. 72, Issue 10
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    journal, February 2015

    • Waters, Michael J.; Brooks, Andrew J.
    • Biochemical Journal, Vol. 466, Issue 1
    • DOI: 10.1042/bj20141293

    XDS
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    • Kabsch, Wolfgang
    • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
    • DOI: 10.1107/s0907444909047337

    Robust single-particle tracking in live-cell time-lapse sequences
    journal, July 2008

    • Jaqaman, Khuloud; Loerke, Dinah; Mettlen, Marcel
    • Nature Methods, Vol. 5, Issue 8
    • DOI: 10.1038/nmeth.1237

    Use of Non-crystallographic Symmetry in Protein Structure Refinement
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    • Kleywegt, G. J.
    • Acta Crystallographica Section D Biological Crystallography, Vol. 52, Issue 4
    • DOI: 10.1107/s0907444995016477

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    • Sergé, Arnauld; Bertaux, Nicolas; Rigneault, Hervé
    • Nature Methods, Vol. 5, Issue 8
    • DOI: 10.1038/nmeth.1233

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    • Wilmes, Stephan; Beutel, Oliver; Li, Zhi
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    • DOI: 10.1083/jcb.201412049

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    • Murshudov, Garib N.; Skubák, Pavol; Lebedev, Andrey A.
    • Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
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    • DOI: 10.1038/26773

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    • Kai, Masayuki; Motoki, Kazuhiro; Yoshida, Hideaki
    • Nature Biotechnology, Vol. 26, Issue 2
    • DOI: 10.1038/nbt1376

    An introduction to data reduction: space-group determination, scaling and intensity statistics
    journal, March 2011

    • Evans, Philip R.
    • Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
    • DOI: 10.1107/s090744491003982x

    Rapid Transfer of Transmembrane Proteins for Single Molecule Dimerization Assays in Polymer-Supported Membranes
    journal, September 2014

    • Roder, Friedrich; Wilmes, Stephan; Richter, Christian P.
    • ACS Chemical Biology, Vol. 9, Issue 11
    • DOI: 10.1021/cb5005806

    Designing Repeat Proteins: Well-expressed, Soluble and Stable Proteins from Combinatorial Libraries of Consensus Ankyrin Repeat Proteins
    journal, September 2003


    Crystal Structure of the Marburg Virus VP35 Oligomerization Domain
    journal, November 2016

    • Bruhn, Jessica F.; Kirchdoerfer, Robert N.; Urata, Sarah M.
    • Journal of Virology, Vol. 91, Issue 2
    • DOI: 10.1128/jvi.01085-16

    Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard
    journal, December 2007

    • Terwilliger, Thomas C.; Grosse-Kunstleve, Ralf W.; Afonine, Pavel V.
    • Acta Crystallographica Section D Biological Crystallography, Vol. 64, Issue 1
    • DOI: 10.1107/s090744490705024x

    Low-resolution refinement tools in REFMAC 5
    journal, March 2012

    • Nicholls, Robert A.; Long, Fei; Murshudov, Garib N.
    • Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4
    • DOI: 10.1107/s090744491105606x

    Collaboration gets the most out of software
    journal, September 2013


    Insights into Cytokine–Receptor Interactions from Cytokine Engineering
    journal, March 2015


    Tuning Cytokine Receptor Signaling by Re-orienting Dimer Geometry with Surrogate Ligands
    journal, March 2015


    Isolating and engineering human antibodies using yeast surface display
    journal, July 2006

    • Chao, Ginger; Lau, Wai L.; Hackel, Benjamin J.
    • Nature Protocols, Vol. 1, Issue 2
    • DOI: 10.1038/nprot.2006.94

    Lineage-Specific Hematopoietic Growth Factors
    journal, May 2006


    Functional Mimicry of a Protein Hormone by a Peptide Agonist: The EPO Receptor Complex at 2.8 A
    journal, July 1996


    IL-10 Elicits IFNγ-Dependent Tumor Immune Surveillance
    journal, December 2011


    An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway
    journal, May 2008

    • Rowlinson, Scott W.; Yoshizato, Hideo; Barclay, Johanna L.
    • Nature Cell Biology, Vol. 10, Issue 6
    • DOI: 10.1038/ncb1737

    Designed Ankyrin Repeat Proteins (DARPins): Binding Proteins for Research, Diagnostics, and Therapy
    journal, January 2015


    Features and development of Coot
    journal, March 2010

    • Emsley, P.; Lohkamp, B.; Scott, W. G.
    • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
    • DOI: 10.1107/s0907444910007493

    Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases
    journal, October 2016

    • Akdis, Mübeccel; Aab, Alar; Altunbulakli, Can
    • Journal of Allergy and Clinical Immunology, Vol. 138, Issue 4
    • DOI: 10.1016/j.jaci.2016.06.033

    Interpreting mixed signals: the cell's cytokine conundrum
    journal, October 2011

    • Delgoffe, Greg M.; Murray, Peter J.; Vignali, Dario AA
    • Current Opinion in Immunology, Vol. 23, Issue 5
    • DOI: 10.1016/j.coi.2011.07.013

    Dimerization of the Erythropoietin Receptor Transmembrane Domain in Micelles
    journal, February 2007


    Computational design of self-assembling cyclic protein homo-oligomers
    journal, December 2016

    • Fallas, Jorge A.; Ueda, George; Sheffler, William
    • Nature Chemistry, Vol. 9, Issue 4
    • DOI: 10.1038/nchem.2673

    Interleukin-2 Activity Can Be Fine Tuned with Engineered Receptor Signaling Clamps
    journal, May 2015


    Hematopoietic cytokines
    journal, January 2008


    Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes
    journal, March 2018

    • Sockolosky, Jonathan T.; Trotta, Eleonora; Parisi, Giulia
    • Science, Vol. 359, Issue 6379
    • DOI: 10.1126/science.aar3246

    Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells
    journal, January 2016


    Recent developments in biased agonism
    journal, April 2014


    Ankyrin Repeat:  A Unique Motif Mediating Protein−Protein Interactions
    journal, December 2006

    • Li, Junan; Mahajan, Anjali; Tsai, Ming-Daw
    • Biochemistry, Vol. 45, Issue 51
    • DOI: 10.1021/bi062188q

    Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation
    journal, July 2018

    • Ferrao, Ryan D.; Wallweber, Heidi JA; Lupardus, Patrick J.
    • eLife, Vol. 7
    • DOI: 10.7554/elife.38089

    From DARPins to LoopDARPins: Novel LoopDARPin Design Allows the Selection of Low Picomolar Binders in a Single Round of Ribosome Display
    journal, February 2014

    • Schilling, Johannes; Schöppe, Jendrik; Plückthun, Andreas
    • Journal of Molecular Biology, Vol. 426, Issue 3
    • DOI: 10.1016/j.jmb.2013.10.026

    Overview of the CCP 4 suite and current developments
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