Cytomegalovirus glycoprotein L (Cytomegalo_gL)
Type: Family

Glycoprotein L from Cytomegalovirus serves a chaperone for the correct folding and surface expression of glycoprotein H (gH) . Glycoprotein L is a member of the heterotrimeric gCIII complex of glycoproteins which also includes gH and gO and has an essential role in viral fusion .

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 alpha-, beta-, and gammaherpesviruses/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 internalisation, 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 .

gH is a ~90kDa 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, ~25kDa 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 alpha- and betaherpesviruses, gH/gL binds receptor-binding accessory proteins. In gammaherpesviruses, 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 .

The sequences of the gL domain vary substantially among herpesviruses. For example, gL domains from alphaherpesviruses cannot be aligned at all with those from either beta- or gammaherpesviruses. 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 .