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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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Chicago
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.
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.
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.
MLA
Félix, Jan et al. “Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1.” STRUCTURE 23.9 (2015): 1621–1631. Print.
@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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