The family Parvoviridae is a group of small (18-26nm diameter), non-enveloped,
and autonomously replicating icosahedral viruses containing a single-stranded
linear DNA genome ranging from 4-6 kb in length, with terminal hairpins [E1].
The parvoviral single-stranded DNA genome contains two open reading frames
(ORFs), one encoding nonstructural (NS) proteins, the other capsid proteins.
All parvoviruses encode a nonstructural protein NS1 (termed Rep in adeno-associated virus [AAV]) that is essential for viral DNA replication and
packaging of viral DNA into capsid. It may play other versatile roles, for
example, in the transactivation of viral and cellular gene expression, DNA
damage response, cell cycle arrest, apoptosis, and/or the modulation of innate
immunity. The N-terminus of the parvoviral NS1 protein contains an origin of
replication binding (OBD) domain, also known as a DNA-specific binding domain
or nuclease (NS1-Nuc) domain. Its central region contains a helicase domain
(see <PDOC51206>), which includes an NTP-binding site, and its C-terminus
includes a transactivation domain (TAD). The PV NS1-Nuc domain plays an
important role in the "rolling hairpin" replication of the single-stranded
parvoviral DNA genome: after cellular enzymes have converted the viral genome
into double-stranded DNA, it recognizes origin of replication sequences and
cleaves (i.e., nicks) one strand DNA at a nearby site known as the terminal
resolution site (trs). Since the DNA encountered by NS1 is double-stranded, it
is assumed that binding of NS1 to its target sequences induces strand
separation, allowing for the endonuclease activity of NS1 to cleave at the trs
site [1,2,3,4,5,6,7]. A homologue of parvoviral NS1, U94, is found in human
herpesvirus 6 variants A and B (HHV-6A and HHV-6B, respectively) which do not
replicate by "rolling hairpin" mecanism. U94 has key functions in the virus
life cycle and associated diseases, having demonstrated or putative roles in
virus replication, integration, and reactivation [8,9].
The PV NS1-Nuc domain consists of a central five-stranded antiparallel β-sheet surrounded by clusters of α-helices (see <PDB:4KW3>. The central
β-sheet forms a cleft that embraces the endonuclease active site. The NS1-Nuc domain structure reveals an overall fold that is canonical to the HUH
superfamily of endonucleases that are involved in rolling-circle replication,
which contain signature motif HUH, also known as motif 2, and motif
YUxxYx(2-3)K, also known as motif 3 (where Y is tyrosine, U is hydrophobic
residue, x is any residue, and K is lysine). Divalent metal ions are required
for DNA cleavage activities for the HUH-superfamily of endonucleases. The
catalytic center of HUH-endonucleases is composed of four residues. Unlike the
two characteristic Histidine residues, the third catalytic residue is
changeable (either Glu or His). The fourth residue is a Tyrosine, which is
highly conserved in HUH-endonucleases [2,3,4,5,6,7].
The profile we developed covers the entire PV NS1-Nuc domain.
Rapp J.C. Krug L.T. Inoue N. Dambaugh T.R. Pellett P.E.
Title
U94, the human herpesvirus 6 homolog of the parvovirus nonstructural gene, is highly conserved among isolates and is expressed at low mRNA levels as a spliced transcript.
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