Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex.
Blood. 2011-03-09; 118(1): 60-68
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1. Blood. 2011 Jul 7;118(1):60-8. doi: 10.1182/blood-2011-01-329532. Epub 2011 Mar
Structural insights into the extracellular assembly of the hematopoietic Flt3
Verstraete K(1), Vandriessche G, Januar M, Elegheert J, Shkumatov AV, Desfosses
A, Van Craenenbroeck K, Svergun DI, Gutsche I, Vergauwen B, Savvides SN.
(1)Unit for Structural Biology, Laboratory for Protein Biochemistry and
Biomolecular Engineering (L-ProBE), 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
PMID: 21389326 [Indexed for MEDLINE]