Viroporin

Viroporins are small and usually hydrophobic multifunctional viral proteins that modify cellular membranes, thereby facilitating virus release from infected cells. Viroporins are capable of assembling into oligomeric ion channels or pores in the host cell's membrane, rendering it more permeable and thus facilitating the exit of virions from the cell. Many viroporins also have additional effects on cellular metabolism and homeostasis mediated by protein-protein interactions with host cell proteins. While viroporins are not considered necessary for replication of viruses, they do aid with increased virion spread and viral infection. They are found in a variety of viral genomes but are particularly common in RNA viruses. Many viruses that cause human disease express viroporins. These viruses include hepatitis C virus, HIV-1, influenza A virus, poliovirus, respiratory syncytial virus, and SARS-CoV. Recently, viroporins have been discovered in plant viruses such as turnip mosaic virus, barley yellow striate mosaic virus, and citrus tristeza virus.

Size and structure Viroporins range in size from approximately 100 to 120 amino acids in length and 6-12 kDa in molecular weight. Oligomerization of viroporins most commonly results in tetramers that reside in either the plasma membrane or ER membrane and act as transport channels. Each type of viroporin contains at least one transmembrane alpha helix that interacts with these membranes. Further, viroporins are commonly considered to be integral membrane proteins. Viroporins exhibit extreme variability in their additional residues, with some containing stretches of basic amino acids (Class II viroporins) and others having aromatic amino acids. This variability contributes to diverse functions across viroporins.

Classification Current classification methods group viroporins into two main classes, each with two subgroups, based on their number of transmembrane domains and their endoplasmic reticulum membrane topology.

Class I viroporins All Class I viroporins contain one transmembrane domain that takes on a helical shape. They also contain a short N-terminal domain and a long C-terminal tail. Subclasses of Class I viroporins are divided based on their orientation about the ER membrane. In Class IA viroporins, the short N-terminal domain is located in the ER lumen with the C-terminal tail residing in the cytosol. Class IB viroporins are the opposite, with the N-terminal domain in the cytosol and the C-terminal tail in the ER lumen.

Class II viroporins Class II viroporins have two transmembrane domains, and a basic amino acid loop connects them. This viroporin class primarily originates from polyproteins, a viral replication mechanism where all functional proteins are translated as a part of the same open reading frame (ORF). The ORF also encodes a self-cleaving protease, which cuts the large polyprotein into each of its functional protein parts after translation is completed. Viroporins in this group often have proteolytic precursors with terminal domains known to form peptidases. Class IIA viroporins have their N- and C-terminal ends located in the ER lumen, and these terminals are located in the cytosol in Class IIB viroporins. Viroproins that have more than 2 transmembrane domains (ex. SARS-CoV) or none at all (ex. Rotavirus) do not fit this current classification system, and more research is needed in this area.

Viroporin oligomerization Viroporins cannot reach their functional form until they complete homo-oligomerization, a process by which individual viroporin proteins associate with themselves. This homo-oligomerization often results in formation of tetramers and occurs in two main steps, similar to the process of general membrane protein folding.

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