PROSITE documentation PDOC52024 [for PROSITE entry PS52025]

Alpha-, beta-, and gammaherpesvirus glycoprotein L (gL) domains profiles

Herpesviruses are enveloped, double-stranded DNA viruses that infect a variety of hosts across the animal kingdom [E1]. More than 100 species of herpesviruses are classified into three subfamilies, namely α-, β-, and γherpesviruses/herpesvirinae. Like other enveloped viruses, herpesviruses enter cells by fusing their lipid envelopes with a host cell membrane, either the plasma membrane or the membrane of an endocytic vesicle/endosome after internalization, which releases the viral capsid and associated proteins into the host cytoplasm. Entry of enveloped viruses into a target cell proceeds through a sequence of events that begins with the binding of a viral receptor-binding glycoprotein to a cognate host cell receptor and culminates with membrane fusion by a viral fusogen, a glycoprotein that undergoes large conformational changes to bring apposing membranes into proximity until they fuse. Uniquely, herpesviruses distribute the functions of receptor engagement and membrane fusion across a diverse cast of glycoproteins. Two glycoprotein complexes are conserved throughout the three herpesvirus subfamilies: the trimeric glycoprotein B (gB) that functions as a membrane fusogen and the heterodimeric glycoprotein H/glycoprotein L (gH/gL), the role of which is less clearly defined. The intrinsic structural plasticity of gH/gL enables it to function as a signal integration machine that can accept diverse regulatory inputs and convert them into a "trigger" signal that activates the fusogenic ability of gB [1,2,3,4].

gH is a ~90-kDa glycoprotein with a large ectodomain, a single-spanning transmembrane helix, and a short cytoplasmic tail. Correct folding, trafficking to the cell surface, and function require that gH bind to gL, a soluble, ~25-kDa glycoprotein. gH/gL is a central player in herpesvirus entry. Across all subfamilies, gH/gL connects binding of host cell receptors with membrane fusion. In α- and βherpesviruses, gH/gL binds receptor-binding accessory proteins. In γherpesviruses, gH/gL either binds a receptor-binding accessory protein or directly engages the host cell receptor. In all cases, gH/gL interacts with gB, presumably, relaying the "trigger" signal that leads to the conformational rearrangements that effect membrane fusion [1,2,3,4].

The sequences of the gL domain vary substantially among herpesviruses. For example, gL domains from αherpesviruses cannot be aligned at all with those from either β- or γherpesviruses. The herpesvirus gL domain does not have a stable core. It includes three helices and two β sheets. One four-stranded antiparallel β-sheet forms a six-stranded β-sheet with two strands from gH. Another is a short three-stranded mixed β-sheet. Four cysteines in gL form two disulfide bonds, and all are critical for proper processing and activity of gH/gL. In the structure, the disulfides clearly maintain the proper fold of gL [3,4].

We developed three profiles for the gL domain, one for each subfamily. The first profile covers the entire αherpesvirus gL domain, the second the entire βherpesvirus gL domain, and the third the entire γherpesvirus gL domain.