Identification of Human Nectin-4 and Signaling Lymphocyte Activation Molecule/SLAM as Potential Receptors for the Spike Protein of SARS-CoV-2 and its Variants.

INTRODUCTION: SARS-COV2 Spike protein is critical for virus entry as well as proinflammatory responses in host cells. The Spike epitopes form heteromeric complexes with HLA-DR alleles and Toll-like Receptors 2, 4, and 8. The Receptor Binding Domain of the Spike protein binds with Angiotensin Converting Enzyme2 (ACE2) as the first known host receptor. In this context, the aim is to identify a host cell surface protein as a potential receptor for the SARS-CoV-2 family that not only allows viral entry but also triggers inflammation.

METHODS: Virus Spike Receptor Binding Domain (RBD) sequences, human Nectin4 and Signaling Lymphocyte Activation Molecule (SLAM) (amino acid sequences and corresponding Protein Database: PDB) were used for the in silico experiments cell free digital experiments. The Dimer Packing Quality (FSCOR) for heterodimeric protein/peptide structure formation was determined by using Preddimer software. The construction of PDB files for peptide sequences was performed by Avogadro's software. Schrodinger PyMol software was used for the Molecular Docking and Molecular Dynamics experiments to determine interactions between two unrelated protein/peptide molecules and to generate heterodimeric structures.

RESULTS: The experiments showed the ability of SARS-CoV-2 Spike RBD (constructed PDB: SpRD 2, 5, 7, and 8) to bind human Nectin4 and SLAM, generating heterodimeric structures at pH 7.2 (p < 0.05). Molecular Docking and Molecular Dynamics demonstrated sequence-specific binding patterns between virus RBD fragments (RMSD: 0.05- 1.1 Angstrom) and human Nectin4 (RMSD 32.375 Angstroms) and SLAM (RMSD 27.451 Angstroms) proteins.

DISCUSSION: SARS-CoV-2 Spike forms heterodimeric structures with Nectin4 and SLAM.

CONCLUSION: Computational modeling identifies Nectin4 and SLAM as potential receptors for the virus Spike protein.