Flt3_D3-Flt3_D4 elbow and the absence of homotypic receptor contacts in the Flt3:FL complex. (A) The Flt3_D3-Flt3_D4 elbow. Flt3_D3 (partially shown) and Flt3_D4 are shown in ribbon representation. For clarity purposes only the locations of the atypical disulfide bridges in Flt3_D4 (Cys368-Cys407 and Cys381-Cys391) are indicated. Residues mediating hydrophobic interactions between Flt3_D3 and Flt3_D4 are shown as green sticks. Residues in the Flt3_D3-Flt3_D4 linker (346-348) are shown as yellow spheres centered at their Cα positions. The side chains of residues mediating contacts between the AA′ loop of Flt3_D3 and the C′E loop of Flt3_D4 could not be modeled because of the low resolution of our analysis. The EF loop of Flt3_D4 constituting the “tyrosine corner” around Tyr416 (green sticks) is shown in orange. (B) Sequence conservation of residues involved at the D3-D4 interface in KIT and Flt3 based on comparisons between human and murine Flt3 and KIT sequences. (C) KIT_D3-KIT_D4 orientation in the KIT:SCF complex. Homotypic receptor contacts between tandem ectodomain 4 modules in the KIT:SCF complex are mediated by salt bridges via residues Arg381 and Glu386 residing on the EF loops (orange; PDB entry 2E9W). Residues at the hydrophobic KIT_D3-KIT_D4 interface are shown as green sticks. Residues in the KIT_D3-KIT_D4 linker region (Asp309-Gly311) are shown as yellow spheres. (D) Flt3_D4 displays an atypical EF loop within the RTKIII/V family. The pair of residues mediating the homotypic contacts in KIT_D4 and VEGFR-2_D7 is well conserved in the corresponding domains of all RTKIII/V members but not in Flt3_D4.