(A) Structures of γB3 (dark red, PDB: 5K8R), γB2 (lemon), and γB7 (lime-green), superposed on their EC2 domains from one protomer. The overall head-to-tail mode of interaction is similar for all three structures, however, domain orientations within the γB3 structure are significantly different compared to both γB2 and γB7. (B) Close-up views of the EC2:EC3 interactions in the γB7 (left), γB2 (middle), and γB3 (right) structures. EC2 domains are shown in white and EC3 domains are shown in gray surface representation. Red stars highlight regions in the EC2:EC3 interface that are not in contact. These regions only appear in the γB3 structure. The HEPES molecule at the EC2:EC3 interface of γB3 is shown in red in space filling representation. (C) The relative orientations of EC2:EC3 domain interactions in γB3 (dark red) and γB7 (lime-green) are shown by superposition of their EC2 domains. The HEPES molecule at the EC2:EC3 interface of γB3 is shown in red space filling representation. The HEPES molecule contacts residues in both EC2 and EC3 of γB3. Compared to the EC3 domain of γB7, the γB3 EC3 domain is rotated as indicated by the dark red arrow. (D) Close up view of the HEPES molecule buried in the γB3 EC2:EC3 interface. The γB3 structure is shown in orange (EC3) and dark red (EC2) in cartoon representation, and the HEPES molecule is colored by element and shown in stick depiction. Side chains which interact with the bound HEPES molecule are shown. (E) EC2:EC3 interface residues from the available Pcdh trans dimer structures were binned based on their percent buried surface area (BSA) in the homodimer structures. γB3 shows a much lower number of residues with more than 70% of their surface area buried in the homophilic interaction than any other Pcdh isoform. Chains A and B were used from the γA1 structure, and the α4, α7, β6, and β8structures correspond to PDBs: 5DZW, 5DZV, 5DZX, and 5DZY. (F) Table details the number of residue pairs with a Cα-Cα distance of less than 10 Å between the bound EC2 and EC3 domains in each homodimer. γB3 shows a many fewer contacts in the EC2:EC3 interface than any other Pcdh isoform. (G) Percent buried surface area (BSA) per residue in the EC2:EC3 interfaces of the γB7, γB2, and γB3 structures. Residue numbering corresponds to γB2. Overall, similar residues are buried within all three structures. However, while for the γB2 and γB7 homodimers multiple residues bury 100% of their surface area, for the γB3 homodimer structure no residue buries more than 75% of its surface area.