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Structure. 2012 Apr 4;20(4):676-87. doi: 10.1016/j.str.2012.02.010. Epub 2012 Apr 3.

Structural basis for the dual recognition of helical cytokines IL-34 and CSF-1 by CSF-1R.

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  • 1Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Abstract

Lacking any discernible sequence similarity, interleukin-34 (IL-34) and colony stimulating factor 1 (CSF-1) signal through a common receptor CSF-1R on cells of mononuclear phagocyte lineage. Here, the crystal structure of dimeric IL-34 reveals a helical cytokine fold homologous to CSF-1, and we further show that the complex architecture of IL-34 bound to the N-terminal immunoglobulin domains of CSF-1R is similar to the CSF-1/CSF-1R assembly. However, unique conformational adaptations in the receptor domain geometry and intermolecular interface explain the cross-reactivity of CSF-1R for two such distantly related ligands. The docking adaptations of the IL-34 and CSF-1 quaternary complexes, when compared to the stem cell factor assembly, draw a common evolutionary theme for transmembrane signaling. In addition, the structure of IL-34 engaged by a Fab fragment reveals the mechanism of a neutralizing antibody that can help deconvolute IL-34 from CSF-1 biology, with implications for therapeutic intervention in diseases with myeloid pathogenic mechanisms.

Copyright © 2012 Elsevier Ltd. All rights reserved.

PMID:
22483114
[PubMed - indexed for MEDLINE]
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