English: SORLA ectodomain structure and modes of dimerization. Top panel: Putative structural organization of the SORLA luminal (cytosolic or ectodomain) region. Schematic on the left represents the domain architectures and predicted folding of the full SORLA luminal domain. On the right is a revised AlphaFold model showing secondary and tertiary structures of the compact SORLA ectodomain depicted by the molecular graphics program PyMOL. Both the schematic and the structure are presented with the same color code: VPS10p (green), 10CC (red), YWTD (gray), EGF (orange), CR (turquoise), and 3Fn (light blue). Binding of APP to SORLA occurs by the CR-domains, which are not involved in the dimer formation and likely accessible for ligand interactions. Middle panel: Schematics of two different local (closed) dimers formed by either 3Fn- or VPS10p-domain interfaces. Bottom panel: A model showing how SORLA if forming polymers could engage with the polymeric retromer coat on endosome tubules. The two putative dimer interfaces, one involving the Vps10 domains and one involving the 3Fn domains, are depicted as red and blue asterisks, respectively. The lower figure illustrates how one possible arrangement of these two interfaces, consistent with their relative orientations as predicted by the revised AlphaFold model shown in the top right panel, could lead to polymerization of SORLA in a way that would both fit with and possibly stabilize the polymer of retromer known to exist on the tubular membrane.