Structural basis of Fusobacterium nucleatum adhesin Fap2 interaction with receptors on cancer and immune cells

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Item Type:	Preprint
Title:	Structural basis of Fusobacterium nucleatum adhesin Fap2 interaction with receptors on cancer and immune cells
Creators Name:	Schöpf, F., Marongiu, G.L., Milaj, K., Sprink, T., Kikhney, J., Moter, A. and Roderer, D.
Abstract:	The intestinal microbiome (IM) is decisive for the human host’s health. Numerous microbiota drive the progression of colorectal cancer (CRC), the third-most common cancer worldwide. The Gramnegative Fusobacterium nucleatum (Fn) is overrepresented in the IM of CRC patients and has been correlated with the emergence, progression, and metastasis of tumors. A key pathogenic factor of Fn is the adhesin Fap2, an autotransporter protein that facilitates association to cancer and immune cells via two receptors, the glycan Gal-GalNAc and the T-cell protein TIGIT, respectively. The latter interaction leads to deactivation of immune cells. Mechanistic details of the Fap2/TIGIT interaction remain elusive due to the lack of high-resolution structural data. Here, we report a system to recombinantly express functional Fap2 on the Escherichia coli surface, which interacts with Gal-GalNAc on cancer cells and with purified TIGIT with submicromolar affinity. Cryo-EM structures of Fap2, alone and in complex with TIGIT, show that the ~50 nm long rod-shaped Fap2 extracellular region binds to TIGIT on its membrane-distal tip via an extension of a β-helix domain. Moreover, by combining structure predictions, cryo-EM, docking and MD simulations, we identified a binding pit for Gal-GalNAc on the tip of Fap2. Our data represent the first purification and high-resolution structural analysis of a Fn autotransporter adhesin and its receptor association.
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2024.02.28.582045
Date:	1 March 2024
Official Publication:	https://doi.org/10.1101/2024.02.28.582045

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