Title : Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5 /6
Abstract :
LDL receptor-related proteins 5 and 6 ( LRP5 /6) are coreceptors for Wnt growth factors , and also bind Dkk proteins , secreted inhibitors of Wnt signaling
The LRP5 /6 ectodomain contains four β-propeller/EGF-like domain repeats
The first two repeats, LRP6 ( 1-2 ), bind to several Wnt variants , whereas LRP6 ( 3-4 ) binds other Wnts
We present the crystal structure of the Dkk1 C-terminal domain bound to LRP6 ( 3-4 ), and show that the Dkk1 N-terminal domain binds to LRP6 ( 1-2 ), demonstrating that a single Dkk1 molecule can bind to both portions of the LRP6 ectodomain and thereby inhibit different Wnts
Small-angle X-ray scattering analysis of LRP6 ( 1-4 ) bound to a noninhibitory antibody fragment or to full-length Dkk1 shows that in both cases the ectodomain adopts a curved conformation that places the first three repeats at a similar height relative to the membrane
Thus, Wnts bound to either portion of the LRP6 ectodomain likely bear a similar spatial relationship to Frizzled coreceptors