PROSITE documentation PDOC52115

Filovirus nucleoprotein (NP) N-terminal core 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), five species of Ebolavirus, i.e. Zaire (EBOV), Reston (RESTV), Sudan (SUDV), Tai Forest (TAFV, also known as Ivory Coast) and Bundibugyo (BDBV), and Cuevavirus (Lloviu virus [LLOV]). In each of these viruses the ssRNA encodes at least seven 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 oligomerizes into helical filaments found at the core of the virion, encapsidates the viral RNA genome, and serves as a scaffold for additional viral proteins within the viral nucleocapsid. NP has an N-terminal region that is sufficient for self-assembly and single-stranded RNA (ssRNA) packaging and a C-terminal region that is largely unstructured and which is implicated in several protein-protein interactions and required for the interactions with other nucleocapsid components (see <PDOC52113>). The newly synthesized NPs must be prevented from indiscriminately binding to noncognate RNAs. A peptide from VP35 termed NP binding peptide (NPBP) (see <PDOC52111>) binds the N-terminal core domain of NP and obstructs the oligomerization of NP. As the RNA binding by NP is believed to be non-specific but is nonetheless a high-affinity interaction, RNA binding by NP is likely to occur concurrently with or in very rapid succession to the removal of the VP35 NPBP and oligomerization of NP in order to ensure that only viral RNA and not cellular RNA is encapsidated [1,2,3,4,5].

The NP N-terminal core domain is principally composed of α-helices and contains an N-terminal head lobe and a C-terminal foot lobe connected by a flexible hinge located within the head lobe (see <PDB:7YPW>). The N-terminal head and C-terminal foot lobes together form a bi-lobed structure, with a positive-charged RNA binding groove between the two lobes. The foot lobe of the NP core constitutes a hydrophobic pocket occupied by the VP35 NPBP. The bi-lobed structure is preceded by an N-terminal arm essential for the oligomerization of filovirus NPs. The helix eta1 on the N-terminal arm of the NP(n) binds to the hydrophobic pocket located in the foot lobe of the NP(n+1) [1,2,3,4,5].

The profile we developed covers both the filovirus NP N-terminal core domain and the preceding N-terminal oligomerization arm.