PROSITE documentation PDOC52109

Filovirus large (L) protein C-terminal domain (CTD) profile

The family Filoviridae [E1], which includes Ebola virus (EBOV) and Marburg virus (MARV), is part of the order Mononegavirales together with the Rhabdoviridae, the Pneumoviridae, the Paramyxoviridae and the Bornaviridae families, etc. EBOV and MARV belong to different filoviral genera, the Ebolavirus and Marburgvirus respectively, and they are genetically distinct. So far, six species of Ebolavirus have been identified, including Bundibugyo, Reston, Sudan, Tai Forest, Bombali, and Zaire Ebolavirus, while Lake Victoria Marburgvirus is the only member in Marburgvirus. These viruses are enveloped, non-segmented negative-sensed RNA viruses (nsNSVs) capable of causing severe hemorrhagic fevers with high mortality rates. The negative-sense RNA genome of filoviruses encodes the following seven major proteins: the nucleoprotein (NP), the viral proteins VP35 and VP40, the glycoprotein (GP), the viral proteins VP30 and VP24, and the "large" protein (L). L proteins were found to catalyze all enzymatic reactions required for viral mRNA synthesis and processing (capping, cap methylation, and polyadenylation). They contain three catalytic domains, the RNA-dependent RNA polymerase (RdRp) (see <PDOC50507>), the GDP polyribonucleotidyl transferase (PRNTase) (see <PDOC52108>, and methyltransferase (MTase) (see <PDOC51555>), in addition to two structural domains, the connecting domain (CD), between the PRNTase and MTase domains, and C-terminal domain (CTD-domain). The L protein MTase sequentially catalyzes the RNA cap structure methylation at the ribose 2'-O and guanosine N-7 positions. It also catalyzes cap-independent methylation, leading to internal adenosine 2'-O-methylation. Therefore, The filovirus MTase might have evolved toward a dual activity, targeting the cap structure present at the 5' end of mRNA and adenosine residues inside the RNA. The filovirus L CTD, which is enriched in basic amino acids, plays a key role in RNA binding and in turn regulates the different MTase activities. It selectively contributes to the right positioning of RNA in the MTase catalytic site, thereby regulating the different MTase activities of the protein. Consequently, it participates in viral replication and escape of the host innate immunity. Although the CTD domain of the mononegavirus L proteins shows a large degree of diversity in size and sequence, its function as a regulator of the MTase activity might be conserved [1].

The profile we developed covers the entire Filovirus L protein CTD.