A Proposal for a Consolidated Structural Model of the CagY Protein of Helicobacter pylori

CagY is the largest and most complex protein from Helicobacter pylori's type IV secretion system (T4SS) and may participate in the modulation of gastric tissue inflammation. A three-dimensional structure has been reported for only two segments of the protein. To build a more complete model, particularly the region that spans between the outer membrane (OM) and the inner membrane (IM), we employed different approaches, including homology modeling, ab initio, and deep learning techniques. For the long-middle repeat region (MRR), modeling was performed using deep learning techniques and Molecular Dynamics. The modeled segments were assembled into a chain of 1595 aa, and a 14-chain CagY multimer structure was composed by structural alignment. The final multimer structure correlated with previously published struc-tures and allows to show how the multimer may form the T4SS channel through which CagA and other molecules are translocated to gastric epithelial cells. The model further confirmed that MRR, the most polymorphic and complex region of CagY, presents numerous cysteine residues forming disulfide bonds that stabilize the protein and suggest this domain probably functions as a contractile region that may play an essential role in the modulatory activity of CagY on tissue inflammation.