research advances
February 2012 research highlight
Cell signalling: Crystallizing WNT signalling
SBKB [doi:10.1038/nrm3260]
Low-density lipoprotein receptor-related protein 6 (LRP6) is a co-receptor for WNT signalling that can be inhibited by the binding of Dickkopf (DKK) proteins. By solving the crystal structure of portions of the LRP6 ectodomain, in the presence or absence of the DKK1 carboxy-terminal region (DKK1-C), three studies provide insight into the conformation of LRP6 and the DKK1-mediated inhibition of WNT signalling.
The LRP6 ectodomain contains four β-propellers (Ps) connected by epidermal growth factor (EGF)-like (E) domains, which together form the PE repeats P1E1 to P4E4. Cheng et al. determined the crystal structure of P1E1P2E2 and P3E3P4E4 at 2.8 Å, Chen et al. determined the structure of P3E3P4E4 at 1.9 Å and Ahn et al. determined the conformation of LRP6 P1E1 to P4E4 using small-angle X-ray scattering. These studies together elucidate the overall architectures of P1E1P2E2 and P3E3P4E4 domain pairs, as well as key residues at the interfaces between individual PE domains.
But, how does DKK bind these LRP6 repeats? Interestingly, Chen et al. show that the binding of DKK1 to a top surface of LRP6 P3 can inhibit signalling through WNT3A (which binds P3E3P4E4) and WNT1 (which binds P1E1P2E2). Cheng et al. and Ahn et al. solved the crystal structure of human LRP6 P3E3P4E4 in complex with DKK1-C at 3.1 Å and 2.8 Å, respectively. Both studies found that DKK1-C interacts with the top surface of P3E3, consistent with the finding by Chen et al. that DKK1 binds to the top surface of LRP6 P3. Cheng et al. propose that DKK1-C might also interact with the top surface of structurally similar P1E1. However, by using binding assays, Ahn et al. revealed that the DKK1 amino-terminal region actually associates with P1E1P2E2. This finding, that DKK1 binds both portions of LRP6 in a bipartite manner, explains why it can inhibit signalling by WNTs that bind different LRP6 PE repeat pairs.
Together, these studies shed new light on the mechanics of WNT signalling and on how DKK1 inhibits this pathway.
