The trimeric structures of the extracellular domains of FAM171A1 and FAM171A2 neuronal proteins belong to a novel structural superfamily

Cell surface molecules play fundamental roles in cell-cell communication, attraction, or repulsion, and when expressed in neurons they are often implicated in neurological disorders. FAM171 is a family of three type-I transmembrane domain cell surface proteins (FAM171A1, FAM171A2, and FAM171B) expressed in several human tissues and especially enriched in the brain. Recent findings suggest that FAM171A1 transduces signals between the cell surface and the cytoskeleton. Genetic evidence links FAM171A1 to multiple cancers and FAM171A2 to neurodegenerative diseases, including Alzheimers and Parkinsons diseases. Despite multiple connections with severe human diseases, no information is currently available on their neuronal expression, their structure, or oligomerization. Here we show that, structurally, the monomeric ectodomains of human FAM171A1 and FAM171A2 has a new architecture with a novel combination of two domains. Furthermore, their ectodomains oligomerize to form an equilateral trimer. In addition, the ectodomain of FAM171A1 has the propensity to form larger trimer-trimer assemblies at high concentrations. In the adult mouse brain, Fam171a1 and Fam171a2 mRNAs are broadly distributed in the hippocampus, with predominant expression in excitatory neurons and additional expression in inhibitory neurons. At the protein level, mouse Fam171a1 and Fam171a2 are mainly localized to the hippocampal neuropil, suggesting localization to neuronal processes. Together, these results provide novel insights into the structure and oligomerization of the extracellular domain of FAM171A1 and FAM171A2, suggesting important roles in ligand binding and signaling.