VEEV E2 glycoprotein (aa 348-701) [His]

Alphaviruses are important mosquito-borne pathogens in the virus classification group IV (+) ssRNA virus family Togaviridae, causing localized outbreaks and human epidemics. Alphaviruses can be divided into two separate subgroups: old world (OW) and new world (NW). Venezuelan equine encephalitis virus (VEEV) belongs to the New World alphavirus, which is transmitted by mosquitoes and circulates in rodents. It can cause disease in horses and humans and is characterized by a febrile illness that may progress to encephalitis. The prevalent strains of VEEV are categorized into subtypes ID, IE, and II-VI. In humans, VEEV causes moderate flu-like symptoms, including fever, headache, myalgia, fatigue, nausea, and pharyngitis. In a small number of cases, encephalitis leads to severe neurologic complications such as confusion, convulsions, photophobia, and coma, which are fatal in about 1% of cases. The progression of the disease to encephalitis can lead to long-term neurological deficits.

VEEV is approximately 70 nm in diameter and has T=4 icosahedral symmetry. The viral RNA is encapsulated by a 240-copy viral capsid protein bound to the N-terminus of the protein. At the C-terminus, the capsid binds to the E2 glycoprotein. Glycoproteins E1 and E2 form heterodimers and trimers with other E1/E2 dimers and protrude from the viral envelope obtained from the host cell membrane during germination.

Figure 1. 3D reconstruction of VEEV
(Source: Zhang R, et al. 2011)

The genome is 11.5kb in length and has two reading frames. The RNA has a 5' cap and a 3' poly-A tail and forms a stem-loop structure at the 5' end that serves as a promoter of replication. The first reading frame begins near the 5' end and encodes four nonstructural proteins (nsP1-4), which are translated into a large polyprotein named P1234. nsP1 is involved in the process of mRNA capping to protect the RNA from cellular nucleases. nsP2 is responsible for regulating the packaging of the viral genome into infectious viral particles. nsP3 interacts with the host and influences viral replication. nsP4 is the RNA-dependent RNA polymerase. Together, these proteins form the enzymatic structures required to transcribe and replicate the viral genome. The second reading frame begins in the center of the genome and is controlled by the 26S promoter on negative-strand RNA, encoding structural proteins including capsid, E1 and E2 envelope proteins. E2 protein is glycosylated and is responsible for receptor-mediated endocytosis. It is not only involved in cell attachment, but also a necessary condition for virus budding. The assembled nucleocapsid migrates to the cell surface and interacts with the C-terminal cytoplasmic domain of E2. This interaction itself provides enough energy for the virus to germinate from the cell.

Figure 2. VEEV particle structure and genome organization
(Source: Han L, et al. 2023)

Venezuelan equine encephalitis virus E2 glycoprotein
Venezuelan equine encephalitis virus envelope glycoprotein 2
VEEV E2