PROSITE documentation PDOC51520 [for PROSITE entry PS51520]

Alphavirus nsp2 protease (nsp2pro) domain profile

The family of αviruses includes 26 known members. They infect a variety of hosts including mosquitoes, birds, rodents and other mammals with worldwide distribution. αviruses also pose a potential threat to human health in many area. For example, Venezuelan Equine Encephalitis Virus (VEEV) causes encephalitis in humans as well as livestock in Central and South America, and some variants of Sinbis Virus (SIN) and Semliki Forest Virus (SFV) have been found to cause fever and arthritis in humans [1].

αviruses possess a single-stranded RNA genome of approximately 12 kb [E1]. The genomic RNA of αviruses is translated into two polyproteins that, respectively, encode structural proteins and nonstructural proteins. The nonstructural proteins may be translated as one or two polyproteins, nsp123 or nsp1234, depending on the virus. These polyproteins are cleaved to generate nsp1, nsp2, nsp3 and nsp4 by a protease activity that resides within nsp2. The nsp2 protein of αviruses has multiple enzymatic acivities. Its N-terminal domain has been shown to possess ATPase and GTPase activity, RNA helicase activity and RNA 5'-triphosphatase activity. The C-terminal nsp2pro domain of nsp2 is responsible for the regulation of 26S subgenome RNA synthesis, switching between negative- and positive-strand RNA synthesis, targeting nsp2 for nuclear transport and proteolytic processing of the nonstructural polyprotein [1,2]. The nsp2pro domain is a member of peptidase family C9 of clan CA [E2].

The nsp2pro domain consists of two distinct subdomains (see <PDB:2HWK>). The nsp2pro N-terminal subdomain is largely α-helical and contains the catalytic dyad cysteine and histidine residues organized in a protein fold that differs significantly from any known cysteine protease or protein folds. The nsp2pro C-terminal subdomain displays structural similarity to S-adenosyl-L-methionine-dependent RNA methyltransferases and provides essential elements that contribute to substrate recognition and may also regulate the structure of the substrate binding cleft [2].

The profile we developed covers the entire nsp2pro domain.