Document Type

Article

Publication Date

2025

DOI

10.21203/rs.3.rs-6474377/v1

Publication Title

Research Square

Pages

39 pp.

Abstract

During infection, Listeria adhesion protein (LAP), a housekeeping enzyme, acts as a tight junction modulator (TJM) through interaction with Hsp60 to facilitate Listeria monocytogenes translocation across the intestinal epithelial barrier. Here, we used purified LAP as a potential TJM to overcome the limiting and variable effects observed by other agents in the class. We structurally determined the LAP interaction alone and in complex with Hsp60 utilizing cryo-EM and computational analysis. LAP structure resolved at 2.83 Å, forms multimeric interlocking dimers and tetramers, and the N-domain interacts with Hsp60, while the C-domain bridges the bacterial surface receptor InlB. The structural studies complement LAP-mediated cyclic peptide drugs (vancomycin and desmopressin) absorption across the intestinal barrier in a mouse model without inducing inflammation or adverse effects on the TJ architecture. This study demonstrates that the LAP-Hsp60 complex is the basis for downstream utilization of LAP or peptide mimetics as promising TJM for improved peroral biologics delivery.

Comments

This is a preprint; it has not been peer reviewed by a journal.

Under review: Nature portfolio

Original Publication Citation

Bhunia, A., Samaddar, M. M., Sun, C., Gallina, N., Irizarry-Tardi, N., Liu, D., Tenguria, S., Drolia, R., Jain, A., Kihara, D., Jiang, W., Kim, K.-H., Cox, A., Ristroph, K., Knipp, G., & Noinaj, N. (2025). LAP-Hsp60 complex modulates epithelial tight junction barrier. Research Square. https://doi.org/10.21203/rs.3.rs-6474377/v1

ORCID

0000-0002-8405-2961 (Drolia)

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