|PROSITE documentation PDOC51876|
Pestiviruses [E1], such has bovine viral diarrhea virus (BVDV) and classical swine fever virus (CSFV), are a considerable cause of livestock disease and pathology. This versatile viral family shows a broad spectrum of strain-specific cytopathogenicity, virulence, infection modes, and persistence among their hosts, comprising cattle, swine sheep and wildlife ruminants. Pestiviruses express their genome as a single polypeptide that is subsequently cleaved into individual proteins by host- and virus-encoded proteases. The pestivirus N-terminal protease Npro is a cysteine autoprotease that cleaves between its own C-terminus and the N-terminus of the core protein. Following the first cleavage reaction, Npro does not possess any proteolytic trans-activity but acts as a viral immediate effector to modulate the host cell's antiviral defenses. The released Npro is thought to suppress the production of the host's antiviral type-I interferon (IFN)-α/β via interfering with interferon regulatory factor (IRF) 3 anf IRF7 signaling, thus preventing induction of the IFN-α/β response to pestivirus infection [1,2].
The pestivirus Npro domain is composed predominantly of β-sheets that adopt a "clam shell"-like protease fold (see <PDB:4H9J>). It can be divided into two distinct subdomains, the catalytic cysteine protease subdomain and the zinc-binding subdomain that is required for interaction with IRF3 and IRF7. The protease subdomain spans the N-terminus and also includes C-terminal residues. It harbors the protease active site along with C-terminal protease cleavage site. The active site of Npro's cysteine protease is formed by a catalytic dyad made of a Cys, the nucleophile, and a His, the general base, that flank the C-terminal cleavage site. The protease subdomain contains mostly coils without regular secondary structure and a single β-sheet. The C-terminus of the Npro domain that constitutes the self-cleavage site is not only bound in the protease active site, but also contributes an integral β-strand to the central β-sheet that makes up the active site. Thus, the C-terminus of Npro occludes the catalytic site following cleavage, inhibiting any trans-activity of the protease and limiting the activity of the enzyme to a single catalytic turnover. The zinc-binding subdomain of Npro folds into a five-stranded antiparallel β sheet with β2-β5 forming a Greek key motif and carries a modified form of the metal binding TRASH motif, i.e. C-x(21)-C-x-D-x-C, that coordinates a single zinc atom. The TRASH motif is located at one end of the β-sheet. The interface between the protease and zinc-binding subdomains is mostly hydrophobic, and the C-terminal subdomain partially covers the final β-strand in the protease subdomain. Due to its unique sequence and catalytic site, the pestivirus Npro forms its own cysteine protease family C53 [1,2,E2].
The profile we developed covers the entire pestivirus Npro domain.Last update:
October 2018 / First entry.
PROSITE method (with tools and information) covered by this documentation:
|1||Authors||Zoegg T. Sponring M. Schindler S. Koll M. Schneider R. Brandstetter H. Auer B.|
|Title||Crystal structures of the viral protease Npro imply distinct roles for the catalytic water in catalysis.|
|2||Authors||Gottipati K. Ruggli N. Gerber M. Tratschin J.-D. Benning M. Bellamy H. Choi K.H.|
|Title||The structure of classical swine fever virus N(pro): a novel cysteine Autoprotease and zinc-binding protein involved in subversion of type I interferon induction.|
|Source||PLoS Pathog. 9:E1003704-E1003704(2013).|