(A) Molecular surface representation of the closed (left) and exposed (right) Pcdh19-I1 antiparallel dimer. Interfacing residues are colored according to sequence conservation among 102 species (Figure 5—figure supplement 2 and Figure 5—source data 1). Most of them are highly conserved. Labels as in Figure 2B. (B) Antiparallel Pcdh19 EC1-4 dimer shown as in (A), with interfacing residues colored by sequence conservation among selected members of the non-clustered δ1- and δ2-protocadherins, as well as selected α, β, and γ clustered protocadherins (Figure 5—figure supplement 3 and Figure 5—source data 2). (C) Location of interfacing residues for Pcdh19, Mm pcdhγC3, Mm pcdhα4 and α7, Mm pcdhγA1, and Mm pcdhβ6 and β8, mapped onto the Pcdh19 topology diagram. Shared structural motifs involved in binding include: The F-G loop along with the beginning of β strands A, G and C in EC1; the A-B loop, most of β strand B, the D-E loop, and the beginning of β strand E in EC2; the EC2-3 linker; the C-D loop, parts of β strands F and G and the F-G loop in EC3; the loop within β strand A, β strand B, and the D-E loop in EC4. Red/orange circles indicate sites mutated in PCDH19-FE. Common contact zones in EC1 and EC3, as well as EC2 and EC4, are highlighted with a brown background. See also Figure 5—figure supplement 1–5.