Fig. 1

Neuropilin 1 structure and ligands. NRP1 consists of a large 835 aa extracellular domain, short transmembrane (23 aa) domain, and cytoplasmic (44 aa) portion. Semaphorins 3A and 4A bind to the a1/a2 domain (also termed CUB domain due to its homology to complement proteins C1r and C1s), whereas VEGF₁₆₅, heparan sulphate, TGFb, hepatocytes growth factor (HGF), placental growth factor (PlGF), and SARS-CoV-2 Spike S1 protein bind to the b1/b2 domain (also termed as a coagulation factor homology domain). The a and b domains are critical for binding to the corresponding ligand, whereas the c domain (mephrin or MAM) is important for receptor homodimerization and heterodimerization with Plexin family members. Tm-transmembrane domain. The S1/S2 boundary of the SARS-CoV-2 Spike protein includes the cleavage site for the subtilisin-like host cell protease furin which is expressed in all human tissues. Cleaved S1 through its C-end rule or CendR motif (C-terminal basic sequence motif) directly binds to the b1/b2 domain of NRP1. This binding promotes virus entry and infection