Stuck in the middle: structural insights into the role of the gH/gL heterodimer in herpesvirus entry

Enveloped viruses enter cells by fusing the viral and cellular membranes, and most use a single viral envelope protein that combines receptor-binding and fusogenic functions. In herpesviruses, these functions are distributed among multiple proteins: the conserved fusion protein gB, various non-conserved receptor-binding proteins, and the conserved gH/gL heterodimer that curiously lacks an apparent counterpart in other enveloped viruses. Recent structural studies of gH/gL from HSV-2 and EBV revealed a unique complex with no structural or functional similarity to other viral proteins. Here we analyzed gH/gL structures and highlighted important functional regions. We propose that gH/gL functions as an adaptor that transmits the triggering signals from various non-conserved inputs to the highly conserved fusion protein gB.

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► Herpesviruses require multiple viral proteins to achieve cell entry.
► Receptor-binding and fusogenic functions are distributed among several proteins.
► Conserved gH/gL lacks apparent functional analogs in other viruses.
► HSV-2 and EBV gH/gL structures reveal structural plasticity and important functional regions.
► gH/gL is an adaptor transmitting different triggering signals to conserved fusion protein gB.