Integrative structural analysis of the human LRP2–LRPAP1 complex reveals multiple regulatory sites

The low-density lipoprotein receptor-related protein 2 (LRP2) is an endocytic receptor implicated in the homeostasis of multiple organs. While the low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1) interacts with LRP2, its regulatory role remains elusive. Past studies showed that a single LRPAP1 molecule binds to LRP2 via complement-type repeats. However, many domains of this kind appear unoccupied in LRP2 within the complex. Here, we investigate if multiple LRPAP1 copies could bind the receptor. Using an integrative structural approach, we characterise the human recombinant LRP2 extracellular domain and its complex with LRPAP1, by identifying three additional LRPAP1 binding sites. Notably, two of these sites overlap with ligand-binding regions, suggesting that LRPAP1 may regulate LRP2 ligand-binding activity. Furthermore, we highlight LRPAP1-LRP2 interaction sites unique within the receptor's family and pathogenic LRP2 mutations located at LRP2-LRPAP1 interfaces. Overall, our study redefines the landscape of the LRP2-LRPAP1 interaction, providing insights into its clinical and functional role. Structural studies of the human LRP2-LRPAP1 complex reveal that multiple LRPAP1 molecules can bind to the receptor, highlighting new binding sites that may control how LRP2 binding to other ligands is regulated in health and disease