20 April 2026
Using structural, biochemical and computational approaches, Human Technopole researchers have uncovered how the chaperone LRPAP1 binds to Megalin and regulates its interaction with thyroglobulin and potentially other ligands. The findings are published in Communications Biology.
Megalin (also called LRP2) is a large receptor that helps cells internalise a wide range of molecules, including hormones, vitamin carriers and proteins, through a process known as endocytosis. It is found in several organs such as the kidney, brain, eye and thyroid, where it plays important roles in cellular uptake and tissue homeostasis. In the thyroid, it contributes to hormone production by mediating the uptake of thyroglobulin, the protein precursor of thyroid hormones.
LRPAP1 acts as a folding chaperone for Megalin, among other proteins. Although Megalin has long been known to bind LRPAP1, the details of this interaction have remained unclear.
The Group of Francesca Coscia at Human Technopole reconstructed the structure of the human Megalin extracellular domain and mapped how it interacts with LRPAP1 using a combination of cryo-electron microscopy, crosslinking mass spectrometry and computational modelling. Earlier work suggested that only one LRPAP1 molecule binds to Megalin. This study reveals a much more complex picture: LRPAP1 binds Megalin at four distinct regions, with seven to eight copies associating with each receptor dimer. These findings substantially change our understanding of how the receptor is organised and regulated.
The researchers also found that some of these newly identified LRPAP1 binding regions lie close to, or overlap with, the sites where Megalin binds its cargo molecules. This suggests that LRPAP1 may do more than act as a folding chaperone: it may also control access to the receptor. To test that idea, the researchers examined thyroglobulin, an important thyroid protein known to interact with Megalin. They found that LRPAP1 can displace thyroglobulin from Megalin, providing direct biochemical evidence that LRPAP1 can regulate ligand binding.
The study further confirms that this interaction is sensitive to pH, which may explain how Megalin switches between states in different cellular compartments. The researchers also mapped several disease-associated Megalin mutations to the newly defined LRPAP1 interaction surfaces, offering a structural explanation for how some mutations may disrupt normal receptor regulation. In addition, one of the binding sites appears to be specific to Megalin, distinguishing it from related receptors in the same family.
Beyond the specific findings, the study provides an important technical advance: a recombinant human Megalin system that allows detailed structural and biochemical analysis of a receptor that has been notoriously difficult to study. Together, these results redefine the Megalin–LRPAP1 interaction and deepen our understanding of how this receptor works in health and disease.
Ramanadane, K., Di Ianni, A., Graziadei, A. et al. Integrative structural analysis of the human LRP2–LRPAP1 complex reveals multiple regulatory sites. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09996-y
