Featured Article - March 2014
Short description: Crystal structures of human γ2-adaptin in complex with a peptide from HBV preS1 suggest a path to antivirals.
Hepatitis B virus (HBV) is a potentially lethal liver disease that currently affects over 300 million people worldwide. While protective vaccines are available, there is still no effective treatment for chronic HBV infections. Thus, the development of new antiviral therapies remains an important goal, for which a detailed understanding of host-virus interactions is critical.
During viral maturation and egress, HBV is enveloped by a lipid membrane while transiting through the secretory pathway. This process is dependent on the interaction between the preS1-domain of the long isoform of HBV's surface antigen (HBsAg) protein and the host protein γ2-adaptin. The preS1-domain is exposed on the cytosolic side of the endoplasmic reticulum membrane prior to virion envelopment, and becomes displayed on the surface of the mature virus. Ferguson and colleagues (PSI MPID) recently investigated the interaction between the HBsAg preS1-domain and γ2-adaptin EAR domain (γ2-EAR); the latter is responsible for binding to accessory proteins in the secretory pathway.
First, the authors used NMR spectroscopy to map the interaction surfaces on preS1 and γ2-EAR. Chemical shift perturbations in γ2-EAR were located on a surface equivalent to that of previously mapped peptide-EAR domain interactions. Within preS1, the interaction was located in a linear motif encompassing residues 29–41, with further analyses narrowing this to residues 29–36, a sequence with similarities to canonical EAR-binding motifs.
To obtain a detailed view of the interaction, γ2-EAR was crystalized in its apo form (PDB 4BCX) or bound to either a high-affinity ligand peptide obtained through phage-display screening (PDB 2YMT) or a peptide corresponding to preS1 residues 29–36 (PDB 3ZHF). The structures were solved to resolutions of 2.0, 1.8 and 1.7 Å, respectively. The binding mode of preS1 to γ2-EAR mimicked a two-pin plug motif, with two tryptophan residues separated by a single amino acid instead of the two-residue spacer observed in the canonical interaction with the phage peptide. This binding mode was made possible by a compensating rearrangement within the binding site on γ2-EAR. While NMR and affinity measurements also suggested additional interaction sites on preS1, the phage-derived peptide was sufficient to effectively prevent binding of the full-length preS1 protein to γ2-EAR in vitro.
These findings indicate that HBV interaction with γ2-adaptin—an essential element of virus propagation—could effectively be targeted by a small peptide, suggesting a path for the development of drugs aimed at restricting HBV's access to the cellular trafficking machinery.
M.C. Jürgens et al. The hepatitis b virus preS1 domain hijacks host trafficking proteins by motif mimicry.
Nat Chem Biol. 9, 540-547 (2013). doi:10.1038/nchembio.1294