Blood Journal
Leading the way in experimental and clinical research in hematology

Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex

  1. Kenneth Verstraete1,
  2. Gonzalez Vandriessche2,
  3. Mariska Januar1,
  4. Jonathan Elegheert1,
  5. Alexander V. Shkumatov3,
  6. Ambroise Desfosses4,
  7. Kathleen Van Craenenbroeck5,
  8. Dmitri I. Svergun3,
  9. Irina Gutsche4,
  10. Bjorn Vergauwen1, and
  11. Savvas N. Savvides1
  1. 1Unit for Structural Biology and
  2. 2Unit for Mass Spectrometry and Proteomics, Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Ghent University, Ghent, Belgium;
  3. 3Biological Small Angle Scattering Group, European Molecular Biology Laboratory (EMBL)–Hamburg, Germany;
  4. 4Unit for Virus Host-Cell Interactions, Unité Mixte d'Internationale (UMI) 3265, Université Joseph Fourier (UJF)–EMBL–Centre National de la Recherche Scientifique (CNRS), Grenoble, France; and
  5. 5Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Ghent University, Ghent, Belgium


The class III receptor tyrosine kinase (RTKIII) Fms-like tyrosine kinase receptor 3 (Flt3) and its cytokine ligand (FL) play central roles in hematopoiesis and the immune system, by establishing signaling cascades crucial for the development and homeostasis of hematopoietic progenitors and antigen-presenting dendritic cells. However, Flt3 is also one of the most frequently mutated receptors in hematologic malignancies and is currently a major prognostic factor and clinical target for acute myeloid leukemia. Here, we report the structural basis for the Flt3 ligand-receptor complex and unveil an unanticipated extracellular assembly unlike any other RTKIII/V complex characterized to date. FL induces dimerization of Flt3 via a remarkably compact binding epitope localized at the tip of extracellular domain 3 of Flt3, and it invokes a ternary complex devoid of homotypic receptor interactions. Comparisons of Flt3 with homologous receptors and available mutagenesis data for FL have allowed us to rationalize the unique features of the Flt3 extracellular assembly. Furthermore, thermodynamic dissection of complex formation points to a pronounced enthalpically driven binding event coupled to an entropic penalty. Together, our data suggest that the high-affinity Flt3:FL complex is driven in part by a single preformed binding epitope on FL reminiscent of a “lock-and-key” binding mode, thereby setting the stage for antagonist design.

  • Submitted January 7, 2011.
  • Accepted February 28, 2011.
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