PROSITE documentation PDOC52113

Filovirus nucleoprotein C-terminal (NP-Ct) domain profile

Viral hemorrhagic fevers (VHFs) constitute a group of severe illnesses in which the vascular system is damaged with accompanying internal bleeding, while regulatory functions of the body are critically impaired. Several distinct families of viruses cause VHF, with varying disease severity. The most dangerous VHF, associated with a mortality as high as 90%, is caused by the filoviruses (Filoviridae) [E1]. The Filoviridae family of negative-sense, single-stranded RNA (ssRNA) viruses is comprised of two species of Marburgvirus (MARV and RAVV) and five species of Ebolavirus, i.e. Zaire (EBOV), Reston (RESTV), Sudan (SUDV), Tai Forest (TAFV, also known as Ivory Coast) and Bundibugyo (BDBV). In each of these viruses the ssRNA encodes seven distinct proteins, most of which have multiple functions. Two of them are associated with the membrane: the glycoprotein (GP), which is a transmembrane protein, and VP40, which is associated with the inner surface of the membrane. The remaining five principal proteins [i.e. the nucleoprotein (NP), VP35, VP30, VP24 and RNA polymerase (L)] all interact with ssRNA to form the nucleocapsid. NP is the most abundant viral protein in the infected cell and within the viral nucleocapsid. It is tightly associated with the viral RNA in the nucleocapsid, and during the lifecycle of the virus is essential for transcription, RNA replication, genome packaging and nucleocapsid assembly prior to membrane encapsulation. NP has an N-terminal region that is engaged in packaging the ssRNA and a C-terminal region that is largely unstructured and which is implicated in several protein-protein interactions. This C-terminal region contains a unique globular domain (NP-Ct) which shows no homology to any known proteins and is purported to be a hub for protein-protein interactions within the nucleocapsid. NP-Ct is necessary for formation of inclusion bodies (IBs), cytoplasmic sites of nucleocapsid formation and RNA replication, housing key steps in the virus life cycle. NP-Ct is also required for the production of infectious virus-like particles (VLPs) [1,2,3].

The NP-Ct domain shows relatively low amino-acid sequence conservation. Its structure reveals a novel tertiary fold that is distantly reminiscent of the β-grasp architecture. At its N-terminus, NP-Ct contains an antiparallel pair of α-helices (αA and αB) followed by two β-strands arranged in an antiparallel hairpin (β1 and β2). A stretch of irregular but structured polypeptide chain leads to a short α-helix (αC) at the other extremity of the oblong molecule, followed by another β-hairpin (β3 and β4) and a C-terminal α-helix, αD. The latter appears to be a critical element of the structure, as it runs through the center of the molecule, providing a scaffold around which most of the remainder of the molecule is folded. Residues that belong to the αD helix make contact with the αB helix, with both β-hairpins and with the coil structure connecting the two β-hairpins (see <PDB:4QAZ>) [1,2].

The profile we developed covers the entire filovirus NP-Ct domain.