Flt3 ligand structure and unexpected commonalities of helical bundles and cystine knots

Human Flt3 ligand (Flt3L) stimulates early hematopoiesis by activating a ty pe III tyrosine kinase receptor on primitive bone marrow stem cells. The cr ystal structure of soluble Flt3L reveals that it is a homodimer of two shor t chain cc-helical bundles. Comparisons of structure-function relationships of Flt3L with the homologous hematopoietic cytokines macrophage colony sti mulating factor (MCSF) and stem cell factor (SCF) suggest that they have a common receptor binding mode that is distinct from the paradigm derived fro m the complex of growth hormone with its receptor. Furthermore, we identify recognition features common to all helical and cystine-knot protein ligand s that activate type III tyrosine kinase receptors, and the closely related type V tyrosine kinase receptors.