Nhu Dang (Harvard University)| Elizabeth May (Harvard University)| Rachelle Gaudet (Harvard University)
Protocadherins are membrane proteins that play important roles in brain wiring and neuronal communications. They achieve their functions by interacting with each other across the intercellular space. Within the two largest groups of protocadherins, the δ-protocadherins and clustered protocadherins, individual proteins differ in their structures and protein-protein interaction specificity. Cell-based data show that each clustered protocadherin only interacts with the same clustered protocadherin isoform on the opposite cell membrane (homophilic trans interaction). On the other hand, non-cell-based biophysics data show that some δ-protocadherins interact with different δ-protocadherin isoforms on the opposite side (heterophilic trans interaction). We hypothesize that the spatial expression of clustered and δ-protocadherins in vivo helps to explain this difference. We analyzed publicly available datasets to determine the expression patterns of δ-protocadherins in brain tissues. We found that most δ-protocadherins that can interact heterophilically are expressed in different tissues, while some δ-protocadherins that interact strictly homophilically are co-expressed in the same tissue. Our results suggest that the δ-protocadherins that have the biochemical capacity to interact heterophilically are expressed in spatially distinct tissues so that only homophilic interactions are possible. Multiple structures of protocadherins have been published to help to explain their trans interaction features. However, a comprehensive comparison of all the trans interface structures available to date has not yet been done. We collated all trans interface protocadherin structures and created a database that facilitates the comparative analysis of protocadherins’ trans interactions. The results of this analysis will help us predict the trans interaction specificity of unpublished structures and understand how certain residue mutations might alter protocadherins’ trans interaction specificity.