Title : Structural insights into the extracellular assembly of the hematopoietic
Flt3 signaling complex
Abstract :
- The class III receptor tyrosine kinase (RTK III ) Fms-like tyrosine kinase receptor 3 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 RTK III /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