PROSITE documentation PDOC51876
Pestivirus N-terminal protease (Npro) domain profile


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.


Technical section

PROSITE method (with tools and information) covered by this documentation:

PV_NPRO, PS51876; Pestivirus N-terminal protease Npro domain profile  (MATRIX)


1AuthorsZoegg T. Sponring M. Schindler S. Koll M. Schneider R. Brandstetter H. Auer B.
TitleCrystal structures of the viral protease Npro imply distinct roles for the catalytic water in catalysis.
SourceStructure 21:929-938(2013).
PubMed ID23643950

2AuthorsGottipati K. Ruggli N. Gerber M. Tratschin J.-D. Benning M. Bellamy H. Choi K.H.
TitleThe structure of classical swine fever virus N(pro): a novel cysteine Autoprotease and zinc-binding protein involved in subversion of type I interferon induction.
SourcePLoS Pathog. 9:E1003704-E1003704(2013).
PubMed ID24146623



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