The mechanism of shared but distinct CSF-1R signaling by the non-homologous cytokines IL-34 and CSF-1

Heli Liu, Cindy Leo, Xiaoyan Chen, Brian R. Wong, Lewis T. Williams, Haishan Lin*, Xiaolin He

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

Interleukin-34 (IL-34) and colony stimulating factor-1 (CSF-1) both signal through the CSF-1R receptor tyrosine kinase, but they have no sequence homology, and their functions and signaling activities are not identical. We report the crystal structures of mouse IL-34 alone and in complex with the N-terminal three immunoglobulin-like domains (D1-D3) of mouse CSF-1R. IL-34 is structurally related to other helical hematopoietic cytokines, but contains two additional helices integrally associated with the four shared helices. The non-covalently linked IL-34 homodimer recruits two copies of CSF-1R on the sides of the helical bundles, with an overall shape similar to the CSF-1:CSF-1R complex, but the flexible linker between CSF-1R D2 and D3 allows these domains to clamp IL-34 and CSF-1 at different angles. Functional dissection of the IL-34:CSF-1R interface indicates that the hydrophobic interactions, rather than the salt bridge network, dominate the biological activity of IL-34. To degenerately recognize two ligands with completely different surfaces, CSF-1R apparently takes advantage of different subsets of a chemically inert surface that can be tuned to fit different ligand shapes. Differentiated signaling between IL-34 and CSF-1 is likely achieved by the relative thermodynamic independence of IL-34 vs. negative cooperativity of CSF-1 at the receptor-recognition sites, in combination with the difference in hydrophobicity which dictates a more stable IL-34:CSF-1R complex compared to the CSF-1:CSF-1R complex.

Original languageEnglish (US)
Pages (from-to)938-945
Number of pages8
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1824
Issue number7
DOIs
StatePublished - Jul 2012

Keywords

  • Colony stimulating factor-1 receptor
  • Growth factor
  • Interleukin-34
  • Ligand/receptor binding
  • Receptor tyrosine kinase
  • X-ray crystallography

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

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