The twist of a peptide bond in a viral protein starts a timer for infection, according to Barbara Eckert, Franz Schmid, and colleagues (Universität Bayreuth, Germany). To be successful, the virus must find its host's receptor before this timer goes off.
Bacterial infection by the phage fd is initiated by its gene-3-protein (G3P), which is folded into a protected conformation that is stable, robust, and fairly resistant to degradation, but not infective. Before infection, G3P must be opened via an initial contact with the bacterial F pilus to expose the binding site for its ultimate receptor, TolA. This opening converts a glutamine–proline bond in the hinge between the two binding domains from the cis to the trans conformation. This (nonnative) trans proline locks G3P in the open, infectious form.
The trans proline bond takes several minutes to isomerize spontaneously back to cis. “The back reaction is so slow because of the peculiar local sequence [glutamine–proline–proline] around the proline,” says Schmid. Now his group shows that this sluggish isomerization gives phage fd enough time to infect the cell.
Mutations at and around the hinge proline that hastened the return to cis reduced viral infectivity, presumably because mutant G3P refolded and thus closed its domains before it found TolA. Indeed, trans-to-cis isomerization abolished G3P binding to TolA. Enzymes that accelerated isomerization also interfered with infection. As open G3P is more protease sensitive, keeping it closed probably protects the virus. It might also improve viral specificity by requiring two host interactions.