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PROSITE documentation PDOC51887

Aphthovirus leader protease (L(pro)) domain profile





Description

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.

Last update:

March 2019 / First entry.

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Technical section

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

APHTHOVIRUS_LPRO, PS51887; Aphthovirus leader protease (L(pro)) domain profile  (MATRIX)


References

1AuthorsLi F. Browning G.F. Studdert M.J. Crabb B.S.
TitleEquine rhinovirus 1 is more closely related to foot-and-mouth disease virus than to other picornaviruses.
SourceProc. Natl. Acad. Sci. U. S. A. 93:990-995(1996).
PubMed ID8577774

2AuthorsHinton T.M. Ross-Smith N. Warner S. Belsham G.J. Crabb B.S.
TitleConservation of L and 3C proteinase activities across distantly related aphthoviruses.
SourceJ. Gen. Virol. 83:3111-3121(2002).
PubMed ID12466488
DOI10.1099/0022-1317-83-12-3111

3AuthorsUddowla S. Pacheco J.M. Larson C. Bishop E. Rodriguez L.L. Rai D.K. Arzt J. Rieder E.
TitleCharacterization of a chimeric foot-and-mouth disease virus bearing a bovine rhinitis B virus leader proteinase.
SourceVirology 447:172-180(2013).
PubMed ID24210112
DOI10.1016/j.virol.2013.08.035

4AuthorsLiu Y. Zhu Z. Zhang M. Zheng H.
TitleMultifunctional roles of leader protein of foot-and-mouth disease viruses in suppressing host antiviral responses.
SourceVet. Res. 46:127-127(2015).
PubMed ID26511922
DOI10.1186/s13567-015-0273-1

5AuthorsShanmugam Y. Muthukrishnan M. Singanallur N.B. Villuppanoor S.A.
TitlePhylogenetic analysis of the leader proteinase (Lpro) region of Indian foot and mouth disease serotype O isolates.
SourceVet. Ital. 51:31-37(2015).
PubMed ID25842211
DOI10.12834/VetIt.164.473.2

6AuthorsGuarne A. Tormo J. Kirchweger R. Pfistermueller D. Fita I. Skern T.
TitleStructure of the foot-and-mouth disease virus leader protease: a papain-like fold adapted for self-processing and eIF4G recognition.
SourceEMBO. J. 17:7469-7479(1998).
PubMed ID9857201
DOI10.1093/emboj/17.24.7469

7AuthorsGuarne A. Hampoelz B. Glaser W. Carpena X. Tormo J. Fita I. Skern T.
TitleStructural and biochemical features distinguish the foot-and-mouth disease virus leader proteinase from other papain-like enzymes.
SourceJ. Mol. Biol. 302:1227-1240(2000).
PubMed ID11183785
DOI10.1006/jmbi.2000.4115

E1Titlehttps://viralzone.expasy.org/98?outline=all_by_species

E2Titlehttps://viralzone.expasy.org/33?outline=all_by_protein

E3Titlehttps://www.ebi.ac.uk/merops/cgi-bin/famsum?family=C28



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