Foot-and-mouth disease virus (FMDV) is arguably the world's most important
pathogen of domesticated animals, capable of causing devastating economic loss
to the cattle, sheep and pig industries in particular. FMDV is a member of the
genus Aphthovirus [E1] in the family Picornaviridae [E2], which also contains
bovine rhinitis A and B viruses, and equine rhinitis A virus (ERAV). The
genome of aphthoviruses consists of a positive sense RNA that codes for a
single polyprotein. Members of the genus Aphthovirus are unusual in having a
leader proteinase (L(pro)) as the first component of the polyprotein. L(pro)
is a papain-like proteinase that self-cleaves from the nascent viral
polyprotein precursor during infection and plays an important role in viral
pathogenesis. L(pro) is known to contribute to virus propagation by
suppressing host antiviral activity. L(pro) has an antagonistic effect on host
antiviral responses via at least three mechanisms. The most well-characterized
mechanism is the cleavage of the host-cell translation initiation factor eIF4G
by L(pro), which shuts off host cap-dependent mRNA translation, and interferon
(IFN) translation may be included. Additionally, L(pro) also directly
suppresses production of IFNs (including type I and type III) at the
transcriptional level, through disrupting the IFN signaling pathway to inhibit
host innate immune responses. Finally, L(pro) can significantly inhibit the
activation of some signaling transduction molecules involved in antiviral
pathways through its deubiquitinating (DUB) and deISGylating (IFN-stimulated
gene 15 (ISG15)-removing) activities. The L(pro) domain forms peptidase family
C28 [E3] of clan CA [1,2,3,4,5,6,7].
The L(pro) domain adopts a minimal papain-like fold with a characteristic
arrangement of its Cys-His-Asp catalytic triad. The L(pro) domain is divided
into two subdomains, with the catalytically essential residues located at the
interface (see <PDB:1QOL>). The first, N-terminal subdomain contains four
α-helices (α1, α2, α3 and α4) and two short antiparallel
β-strands (β1 and β2). The longest α-helices α1 and α3
run perpendicular to each other, with the catalytic Cys being located towards
the N-terminal side of helix α1. The shortest helix α3 runs almost
parallel to α3. The second L(pro) subdomain displays a fold belonging to
the all β-family of proteins, as the only regular secondary structure
elements are contained in a mixed β-sheet formed by one parallel (β3
with β4) and six antiparallel (β4-β9) β-strands. The His and Asp
residues are located near each other within the β-stranded subdomain. The
active site His is maintained in the correct orientation with respect to the
nucleophilic Cys by a hydrogen bond to the side-chain oxygen of the Asp [6,7].
The profile we developed covers the entire aphthovirus L(pro) domain.
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