{PDOC51876}
{PS51876; PV_NPRO}
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* Pestivirus N-terminal protease (Npro) domain profile *
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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)-alpha/beta via interfering with
interferon regulatory  factor  (IRF)  3  anf  IRF7  signaling, thus preventing
induction of the IFN-alpha/beta response to pestivirus infection [1,2].

The pestivirus Npro domain is composed predominantly of beta-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 beta-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 beta-strand to the
central beta-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 beta sheet with beta2-beta5 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
beta-sheet. The  interface between the protease and zinc-binding subdomains is
mostly hydrophobic,  and  the  C-terminal subdomain partially covers the final
beta-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.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: October 2018 / First entry.

[ 1] Zoegg T., Sponring M., Schindler S., Koll M., Schneider R.,
     Brandstetter H., Auer B.
     "Crystal structures of the viral protease Npro imply distinct roles
     for the catalytic water in catalysis."
     Structure 21:929-938(2013).
     PubMed=23643950; DOI=10.1016/j.str.2013.04.003
[ 2] Gottipati K., Ruggli N., Gerber M., Tratschin J.-D., Benning M.,
     Bellamy H., Choi K.H.
     "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."
     PLoS Pathog. 9:E1003704-E1003704(2013).
     PubMed=24146623; DOI=10.1371/journal.ppat.1003704
[E1] https://viralzone.expasy.org/39
[E2] https://www.ebi.ac.uk/merops/cgi-bin/famsum?family=C53

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