Elsevier, Structure, 12(19), p. 1762-1772, 2011
DOI: 10.1016/j.str.2011.10.012
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The hematopoietic Colony Stimulating Factor-1 receptor (CSF-1R or FMS) is essential for the development of diverse cell types central to the immune system. Here we report a structural and mechanistic consensus for the assembly of hematopoietic human and mouse CSF-1:CSF-1R complexes. The EM structure of the complete extracellular assembly of the human CSF-1:CSF-1R complex reveals how receptor dimerization by CSF-1 invokes a ternary complex featuring extensive homotypic receptor contacts that contribute 15-fold to the affinity of the complex, and striking structural plasticity at the extremities of the complex. Small-angle X-ray scattering analysis of unliganded hCSF-1R points to large domain rearrangements upon CSF-1 binding, and provides structural evidence for the relevance of receptor predimerization at the cell-surface. Comparative structural and binding studies of human and mouse CSF-1R complexes, including a quantification of the CSF-1/CSF-1R species cross-reactivity, show that bivalent cytokine binding to receptor is a common denominator in complex formation independent of receptor homotypic interactions.