Highly versatile small virus-encoded proteins in cellular membranes: A structural perspective on how proteins’ inherent conformational plasticity couples with host membranes’ properties to control cellular processes

We investigated several small viral proteins that reside and function in cellular membranes, which belong to the viroporin family because they assemble into ion-conducting oligomers. However, despite forming similar oligomeric structures with analogous functions, these proteins have diverse amino acid sequences. In particular, the amino acid compositions of the proposed channel-forming transmembrane (TM) helices are vastly different—some contain residues (e.g., His, Trp, Asp, Ser) that could facilitate cation transport. Still, other voroporins’ TM helices encompass exclusively hydrophobic residues; therefore, it is difficult to explain their channels’ activity, unless other mechanisms (e.g., involving a negative lipid headgroup) take place. For this study, we selected the M2, Vpu, E, p13II, p7, and 2B proteins from the influenza A, HIV-1, human T-cell leukemia, hepatitis C, and picorna viruses, respectively. We discuss the current knowledge of these proteins’ structures as well as remaining questions about a more comprehensive understanding of their structures, conformational dynamics, and function. Finally, we outline strategies to utilize a multi-prong structural approach to overcome current deficiencies in the knowledge about these proteins. Highlights Small viral proteins encoded homo-oligomerize and function in cellular membranes as ion channels These proteins were combined in the family of viroporins Despite the similarity in their oligomeric structures and functions, these proteins have vastly different primary structures It is imperative to understand how proteins with no homology in their primary structures fulfill similar functions for diverse viruses There is a need for a multi-prong structural approach to explain the structure, conformational dynamics, and function of these proteins