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Structure and assembly mechanism of the signaling complex mediated by human CSF-1

Jan Félix (UGent) , Steven De Munck (UGent) , Kenneth Verstraete (UGent) , Leander Meuris (UGent) , Nico Callewaert (UGent) , Jonathan Elegheert (UGent) and Savvas Savvides (UGent)
(2015) STRUCTURE. 23(9). p.1621-1631
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Abstract
Human colony-stimulating factor 1 receptor (hCSF-1R) is unique among the hematopoietic receptors because it is activated by two distinct cytokines, CSF-1 and interleukin-34 (IL-34). Despite evergrowing insights into the central role of hCSF-1R signaling in innate and adaptive immunity, inflammatory diseases, and cancer, the structural basis of the functional dichotomy of hCSF-1R has remained elusive. Here, we report crystal structures of ternary complexes between hCSF-1 and hCSF-1R, including their complete extracellular assembly, and propose a mechanism for the cooperative human CSF-1:CSF-1R complex that relies on the adoption by dimeric hCSF-1 of an active conformational state and homotypic receptor interactions. Furthermore, we trace the cytokine-binding duality of hCSF-1R to a limited set of conserved interactions mediated by functionally equivalent residues on CSF-1 and IL-34 that play into the geometric requirements of hCSF-1R activation, and map the possible mechanistic consequences of somatic mutations in hCSF-1R associated with cancer.
Keywords
EXPRESSION, IL-34, FMS, MACROPHAGES, ACTIVATION, N-GLYCOSYLATION, FACTOR-I, COLONY-STIMULATING FACTOR, PROTO-ONCOGENE PRODUCT, RECEPTOR TYROSINE KINASES

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Citation

Please use this url to cite or link to this publication:

MLA
Félix, Jan, et al. “Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1.” STRUCTURE, vol. 23, no. 9, 2015, pp. 1621–31.
APA
Félix, J., De Munck, S., Verstraete, K., Meuris, L., Callewaert, N., Elegheert, J., & Savvides, S. (2015). Structure and assembly mechanism of the signaling complex mediated by human CSF-1. STRUCTURE, 23(9), 1621–1631.
Chicago author-date
Félix, Jan, Steven De Munck, Kenneth Verstraete, Leander Meuris, Nico Callewaert, Jonathan Elegheert, and Savvas Savvides. 2015. “Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1.” STRUCTURE 23 (9): 1621–31.
Chicago author-date (all authors)
Félix, Jan, Steven De Munck, Kenneth Verstraete, Leander Meuris, Nico Callewaert, Jonathan Elegheert, and Savvas Savvides. 2015. “Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1.” STRUCTURE 23 (9): 1621–1631.
Vancouver
1.
Félix J, De Munck S, Verstraete K, Meuris L, Callewaert N, Elegheert J, et al. Structure and assembly mechanism of the signaling complex mediated by human CSF-1. STRUCTURE. 2015;23(9):1621–31.
IEEE
[1]
J. Félix et al., “Structure and assembly mechanism of the signaling complex mediated by human CSF-1,” STRUCTURE, vol. 23, no. 9, pp. 1621–1631, 2015.
@article{6973193,
  abstract     = {{Human colony-stimulating factor 1 receptor (hCSF-1R) is unique among the hematopoietic receptors because it is activated by two distinct cytokines, CSF-1 and interleukin-34 (IL-34). Despite evergrowing insights into the central role of hCSF-1R signaling in innate and adaptive immunity, inflammatory diseases, and cancer, the structural basis of the functional dichotomy of hCSF-1R has remained elusive. Here, we report crystal structures of ternary complexes between hCSF-1 and hCSF-1R, including their complete extracellular assembly, and propose a mechanism for the cooperative human CSF-1:CSF-1R complex that relies on the adoption by dimeric hCSF-1 of an active conformational state and homotypic receptor interactions. Furthermore, we trace the cytokine-binding duality of hCSF-1R to a limited set of conserved interactions mediated by functionally equivalent residues on CSF-1 and IL-34 that play into the geometric requirements of hCSF-1R activation, and map the possible mechanistic consequences of somatic mutations in hCSF-1R associated with cancer.}},
  author       = {{Félix, Jan and De Munck, Steven and Verstraete, Kenneth and Meuris, Leander and Callewaert, Nico and Elegheert, Jonathan and Savvides, Savvas}},
  issn         = {{0969-2126}},
  journal      = {{STRUCTURE}},
  keywords     = {{EXPRESSION,IL-34,FMS,MACROPHAGES,ACTIVATION,N-GLYCOSYLATION,FACTOR-I,COLONY-STIMULATING FACTOR,PROTO-ONCOGENE PRODUCT,RECEPTOR TYROSINE KINASES}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1621--1631}},
  title        = {{Structure and assembly mechanism of the signaling complex mediated by human CSF-1}},
  url          = {{http://dx.doi.org/10.1016/j.str.2015.06.019}},
  volume       = {{23}},
  year         = {{2015}},
}

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