There is ample experimental evidence that LRR proteins tend to form quaternary structures with dimerization or multimerization surfaces (Scott et al., 2004; Seiradake et al., 2014). Although it is unclear whether these quaternary complexes are able to dissociate upon ligand binding (McEwan et al., 2006) our FLRT3-LRR/LPHN3-OLF complex is monomeric in solution, indicating that the tendency of FLRT3 to self-associate under concentrated condition (Figure 1D,E, (Seiradake et al., 2014)) is reversed upon binding with LPHN3-OLF. The curved structure of the LRR domain and the exposed β-sheet on the concave side form a large binding surface, which makes the LRR domain a very effective protein-binding motif (Kobe and Kajava, 2001). Although ligand-binding through LRR domains concave surfaces is common, it is not exclusive: for example, UNC5D binds to one side of FLRT2 (Seiradake et al., 2014). It is worth noting that the LRR-OLF interface area appears relatively small with respect to the high affinity of the interaction (Chen et al., 2013). Therefore, beyond the solvent-inaccessibility of interface residues, some key structural features, such as the strong electrostatic surface complementary between the
