Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1.
Structure. 2015-09-01; 23(9): 1621-1631
DOI: 10.1016/j.str.2015.06.019
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1. Structure. 2015 Sep 1;23(9):1621-1631. doi: 10.1016/j.str.2015.06.019. Epub 2015
Jul 30.
Structure and Assembly Mechanism of the Signaling Complex Mediated by Human
CSF-1.
Felix J(1), De Munck S(1), Verstraete K(1), Meuris L(2), Callewaert N(2),
Elegheert J(3), Savvides SN(4).
Author information:
(1)Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE),
Department of Biochemistry and Microbiology, Ghent University, 9000 Ghent,
Belgium; Unit for Structural Biology, VIB Inflammation Research Center, 9052
Ghent, Belgium.
(2)Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE),
Department of Biochemistry and Microbiology, Ghent University, 9000 Ghent,
Belgium; VIB Medical Biotechnology Center, 9052 Ghent, Belgium.
(3)Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE),
Department of Biochemistry and Microbiology, Ghent University, 9000 Ghent,
Belgium.
(4)Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE),
Department of Biochemistry and Microbiology, Ghent University, 9000 Ghent,
Belgium; Unit for Structural Biology, VIB Inflammation Research Center, 9052
Ghent, Belgium. Electronic address: .
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.
Copyright © 2015 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.str.2015.06.019
PMID: 26235028 [Indexed for MEDLINE]