Why does the UL49.5 of herpes simplex 1 virus fail to inhibit the TAP-dependent antigen presentation?

Herpes simplex virus type 1 (HSV-1) is a well-studied herpesvirus that causes a number of human diseases. The HSV-1, like other herpesviruses, produces transmembrane glycoprotein N (gN / UL49.5 protein). Although this protein is conserved throughout the herpesvirus family, little is known about its function in HSV-1. The amino-acid sequence and length of UL49.5 proteins differ between herpesvirus species. It is, therefore, crucial to determine whether and to what extent the spatial structure of UL49.5 orthologs that are TAP inhibitors (i.e., of BoHV-1 virus) differs from that of non-TAP inhibitors (i.e., of HSV-1 virus). As a result, the primary goal of our study was to examine the 3D structure of HSV-1-encoded UL49.5 protein in an advanced model of the endoplasmic reticulum (ER) membrane. Circular dichroism (CD), 2D nuclear magnetic resonance (NMR), and multiple-microsecond all-atom molecular dynamics (MD) simulations in the ER membrane mimetic environment were used to determine the final structure of the HSV-1 UL49.5 protein. According to our findings, the N-terminus of HSV-1 UL49.5 adopts a highly flexible, unordered structure in the extracellular part due to the presence of a large number of Pro and Gly residues. In contrast to the UL49.5 protein from BoHV-1, the transmembrane region of HSV-1-encoded UL49.5 is formed by a single long transmembrane -helix, rather than two helices oriented perpendicularly, while the cytoplasmic part of the protein (C-terminus) has a short unordered structure. Our findings provide experimental structural information on HSV-1-encoded UL49.5 protein and structure-based insight into its lack of biological activity in inhibiting the TAP-independent antigen presentation pathway