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TitleStructure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1.
Journal, issue, pagesStructure, Vol. 23, Issue 9, Page 1621-1631, Year 2015
Publish dateSep 1, 2015
AuthorsJan Felix / Steven De Munck / Kenneth Verstraete / Leander Meuris / Nico Callewaert / Jonathan Elegheert / Savvas N Savvides /
PubMed AbstractHuman 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- ...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.
External linksStructure / PubMed:26235028
MethodsSAS (X-ray synchrotron) / X-ray diffraction
Resolution2.802 - 6.853 Å
Structure data

SASDAR6:
human CSF-1:CSF-1R extracellular signalling complex
Method: SAXS/SANS

PDB-4wrl:
Structure of the human CSF-1:CSF-1R complex
Method: X-RAY DIFFRACTION / Resolution: 2.802 Å

PDB-4wrm:
Structure of the human CSF-1:CSF-1R complex
Method: X-RAY DIFFRACTION / Resolution: 6.853 Å

Chemicals

ChemComp-SIA:
N-acetyl-alpha-neuraminic acid

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
KeywordsCYTOKINE/CYTOKINE RECEPTOR / cytokine-cytokine receptor complex

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