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bioRxiv · 10.1101/2025.06.10.658798

A computational analysis of the glycoprotein LRP1 structure and the role of glycans as quaternary glue

Tuveri, G. M.·Basile, M.·Acosta Gutierrez, S.·Kausas, M.·Tian, X.·Franzese, G.·Ruiz Perez, L.·Battaglia, G.
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Abstract

The low-density lipoprotein receptor-related protein 1 (LRP1) plays a critical role in development and transport across the blood-brain barrier (BBB), yet until now, its molecular architecture remained unresolved due to the absence of an experimentally determined structure. Using homology modeling and neural network-based structure prediction algorithms, complemented with molecular dynamics (MD) simulations, we propose a comprehensive model of LRP1 structures. We observe a natural dimerization mechanism and provide insight into the dynamic behavior of its flexible domains under physiological conditions. We investigated the stability of non-covalent interactions keeping LRP1s and {beta} chains linked together, and found the energy required to break the link is 180{+/-}2 kT. The MD characterization highlights the fundamental role of glycans in the creation of LRP1s quaternary structure, increasing the number of intra-dimeric contacts. This study opens new avenues for targeted drug design strategies, enhancing our molecular understanding of LRP1s receptor-mediated transport in the brain and the key mediation of glycosylation in protein-protein interactions.

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Tuveri, G. M., Basile, M., Acosta Gutierrez, S., Kausas, M., Tian, X., Franzese, G., Ruiz Perez, L., Battaglia, G.. 2025-06-14. A computational analysis of the glycoprotein LRP1 structure and the role of glycans as quaternary glue. https://doi.org/10.1101/2025.06.10.658798

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