Structural Basis for the Dual Recognition of Helical Cytokines IL-34 and CSF-1 by CSF-1R

• Published in: Structure (London) 2012-04, Vol.20 (4), p.676-687
• Main Authors: Ma, Xiaolei, Lin, Wei Yu, Chen, Yongmei, Stawicki, Scott, Mukhyala, Kiran, Wu, Yan, Martin, Flavius, Bazan, J. Fernando, Starovasnik, Melissa A.
• Format: Article
• Language: English
• Subjects: Antibodies, Neutralizing - chemistry; Baculoviridae; Binding Sites; Crystallography, X-Ray; Humans; Immunoglobulin Fab Fragments - chemistry; Interleukins - antagonists & inhibitors; Interleukins - chemistry; Interleukins - genetics; Kinetics; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - metabolism; Macrophage Colony-Stimulating Factor - chemistry; Macrophage Colony-Stimulating Factor - genetics; Models, Molecular; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Proto-Oncogene Proteins c-kit - chemistry; Receptor, Macrophage Colony-Stimulating Factor - chemistry; Receptor, Macrophage Colony-Stimulating Factor - genetics; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Signal Transduction - genetics; Stem Cell Factor - chemistry; Structural Homology, Protein; Thermodynamics
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2012.02.010

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. ► Structure of human IL-34 reveals a dimeric four-helix bundle cytokine fold ► Studies in solution confirm bivalent assembly and high affinity of IL-34 with CSF-1R ► The IL-34/CSF-1R complex structure shares a common architecture with CSF-1/CSF-1R ► CSF-1R employs distinct domain adaptations for binding to IL-34 and CSF-1