Human IL-34 and CSF-1 establish structurally similar extracellular assemblies with their common hematopoietic receptor.
Structure. 2013-04-01; 21(4): 528-539
DOI: 10.1016/j.str.2013.01.018
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1. Structure. 2013 Apr 2;21(4):528-39. doi: 10.1016/j.str.2013.01.018. Epub 2013 Mar
7.
Human IL-34 and CSF-1 establish structurally similar extracellular assemblies
with their common hematopoietic receptor.
Felix J(1), Elegheert J, Gutsche I, Shkumatov AV, Wen Y, Bracke N, Pannecoucke E,
Vandenberghe I, Devreese B, Svergun DI, Pauwels E, Vergauwen B, Savvides SN.
Author information:
(1)Unit for Structural Biology, Laboratory for Protein Biochemistry and
Biomolecular Engineering (L-ProBE), Ghent University, K.L. Ledeganckstraat 35,
9000 Ghent, Belgium.
The discovery that hematopoietic human colony stimulating factor-1 receptor
(CSF-1R) can be activated by two distinct cognate cytokines, colony stimulating
factor-1 (CSF-1) and interleukin-34 (IL-34), created puzzling scenarios for the
two possible signaling complexes. We here employ a hybrid structural approach
based on small-angle X-ray scattering (SAXS) and negative-stain EM to reveal that
bivalent binding of human IL-34 to CSF-1R leads to an extracellular assembly
hallmarked by striking similarities to the CSF-1:CSF-1R complex, including
homotypic receptor-receptor interactions. Thus, IL-34 and CSF-1 have evolved to
exploit the geometric requirements of CSF-1R activation. Our models include
N-linked oligomannose glycans derived from a systematic approach resulting in the
accurate fitting of glycosylated models to the SAXS data. We further show that
the C-terminal region of IL-34 is heavily glycosylated and that it can be
proteolytically cleaved from the IL-34:hCSF-1R complex, providing insights into
its role in the functional nonredundancy of IL-34 and CSF-1.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.str.2013.01.018
PMID: 23478061 [Indexed for MEDLINE]