Viral Glycoproteins

Structure and function of viral glycoproteins

Adsorption of the viral particle to the target cell and its penetration into the cytoplasm are the first steps of the viral replication cycle. Membrane-enveloped viruses like retroviruses use viral glycoproteins embedded into the lipid membrane of their viral particle for these processes. The viral glycoproteins mediate binding to specific cellular receptors on the surface of target cells and catalyze the fusion of viral and cellular lipid membrane to allow release of the viral capsid into the cytoplasm of the target cell so that subsequent steps of the viral replication cycle can be completed. 
Retroviral glycoproteins are usually translated as a precursor protein encoded by the envelope (env) open reading frame (ORF). Cotranslational targeting of the glycoproteins to the secretory pathway is mediated by an N-terminal signal sequence, which generally is co-translationally removed. During its transport to the cell surface the precursor glycoprotein is further processed by cellular proteases into surface (SU) and transmembrane (TM) subunits. The SU subunit is attached to the extracellular domains of the TM subunit through covalent or non-covalent interactions. Most retroviral glycoproteins form trimeric complexes of the SU/TM heterodimer at the viral or cellular membrane. In general the SU subunit contains the receptor binding domain (RBD) for the specific cellular receptor used for entry, whereas the fusion machinery utilized for fusion of viral and cellular lipid membranes during virus entry is located within the TM subunit.
Our research interests are not focused only on the structure and function of the foamy virus (FV) glycoproteins, but also to other viral glycoproteins such as the murine leukemia virus (MLV) Env protein or the vesicular stomatitis virus (VSV) glycoprotein G. 
We have discovered several unique features of the FV glycoprotein in recent years. For example the FV Env protein undergoes a highly unusual biosynthesis. Like other retroviral glycoproteins it is translated as a precursor protein, however, unlike these the cellular signal peptidase complex in the endoplasmic reticulum does not co-translationally processes its N-terminal secretory-pathway targeting signal. The two proteolytic processing events of the FV Env precursor, leading to the generation of leader peptide (LP), SU- and TM subunits, occur only late during the intracellular transport and are mediated by furin or furin-like proteases. In addition, all three Env subunits are incorporated into the lipid membrane of the viral particle, which form highly ordered lattices on the virus particle surface. Another unique feature of the FV Env protein is its essential role late in the viral replication cycle. For the membrane association of the viral capsid and its budding across cellular lipid membranes a specific interaction between FV Gag and Env proteins is required and can not be complemented for by heterologous viral glycoproteins. As one important interaction domain on the viral glycoprotein we could identify a 15 amino acids „budding domain“ containing an evolutionary conserved di-tryptophan motive that is located at the cytoplasmic N-terminus of the LP subunit. 

In regard to the structural and functional analysis of the FV glycoproteins we are interested in, 

• identification and characterization of structural motifs of the glycoproteins involved in intracellular localization, intracellular transport, oligomerization or fusion of viral and cellular lipid membranes;  
• the characterization of the minimal receptor binding domain;  
• the identification of the currently unknown cellular receptor of FVs that seems to be ubiquitously expressed;  
• the characterization of glycoprotein structures essential for release of subviral particles.