Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1

Structure. 2015 Sep 1;23(9):1621-1631. doi: 10.1016/j.str.2015.06.019. Epub 2015 Jul 30.


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 ever-growing 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray*
  • Enzyme Activation
  • Humans
  • Macrophage Colony-Stimulating Factor / chemistry*
  • Macrophage Colony-Stimulating Factor / metabolism*
  • Models, Molecular
  • Phosphorylation
  • Receptor, Macrophage Colony-Stimulating Factor / chemistry*
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism*
  • Scattering, Small Angle
  • Signal Transduction
  • X-Ray Diffraction


  • Macrophage Colony-Stimulating Factor
  • Receptor, Macrophage Colony-Stimulating Factor

Associated data

  • PDB/4WRL
  • PDB/4WRM