Pathways & interactions
Potyvirus NIa protease (NIa-pro) domain (IPR001730)
Short name: Potyv_NIa-pro_dom
- Peptidase S1, PA clan (IPR009003)
- Potyvirus NIa protease (NIa-pro) domain (IPR001730)
Tobacco etch virus (TEV), tomato vein mottling virus (TVMV), and plum pox virus (PPV) are members of the Potyviridae family. The potyvirus genome is a (+) stranded RNA and is translated into a single polyprotein upon infection, which is processed by the virally encoded proteases P1, HC-Pro, and NIa. Most of the cleavage events are performed by NIa (nuclear inclusion protein a) protease (NIa-pro). NIa-pro processes seven sites present in the potyvirus polyprotein, named as A, B, C, D, V, E, and F. NIa-pros obtained from potyviruses have similar structures and functions. The potyvirus NIa-pro has a His-Asp-Cys catalytic triad, which is homologous to the trypsin-like proteases except for Cys replacing Ser. NIa-pros obtained from potyviruses share certain sequence identities; however they recognise distinct amino acid sequences at each recognition sites. Consequently, they cannot recognise the cleavage sites of each other efficiently [PMID: 18024078]. Nia-pro belongs to peptidase family C4. In addition to the catalytic activity NIa-pro possesses also sequence non-specific RNA-binding activity and RNA polymerase (NIb) binding activity [PMID: 12377789].
The potyvirus NIa protein contains the following two domains; the VPg domain at the N terminus and the NIa-pro domain at the C terminus [PMID: 18024078, PMID: 9356344]. The ~250-amino acid NIaPro domain adopts the characteristic two-domain antiparallel beta-barrel fold that is the hallmark of trypsin-like serine proteases, with the catalytic triad residues His, Asp, and Cys located at the interface between domains [PMID: 12377789].
This entry represents the NIa-pro domain.
A cysteine peptidase is a proteolytic enzyme that hydrolyses a peptide bond using the thiol group of a cysteine residue as a nucleophile. Hydrolysis involves usually a catalytic triad consisting of the thiol group of the cysteine, the imidazolium ring of a histidine, and a third residue, usually asparagine or aspartic acid, to orientate and activate the imidazolium ring. In only one family of cysteine peptidases, is the role of the general base assigned to a residue other than a histidine: in peptidases from family C89 (acid ceramidase) an arginine is the general base. Cysteine peptidases can be grouped into fourteen different clans, with members of each clan possessing a tertiary fold unique to the clan. Four clans of cysteine peptidases share structural similarities with serine and threonine peptidases and asparagine lyases. From sequence similarities, cysteine peptidases can be clustered into over 80 different families [PMID: 11517925]. Clans CF, CM, CN, CO, CP and PD contain only one family.
Cysteine peptidases are often active at acidic pH and are therefore confined to acidic environments, such as the animal lysosome or plant vacuole. Cysteine peptidases can be endopeptidases, aminopeptidases, carboxypeptidases, dipeptidyl-peptidases or omega-peptidases. They are inhibited by thiol chelators such as iodoacetate, iodoacetic acid, N-ethylmaleimide or p-chloromercuribenzoate.
Clan CA includes proteins with a papain-like fold. There is a catalytic triad which occurs in the order: Cys/His/Asn (or Asp). A fourth residue, usually Gln, is important for stabilising the acyl intermediate that forms during catalysis, and this precedes the active site Cys. The fold consists of two subdomains with the active site between them. One subdomain consists of a bundle of helices, with the catalytic Cys at the end of one of them, and the other subdomain is a beta-barrel with the active site His and Asn (or Asp). There are over thirty families in the clan, and tertiary structures have been solved for members of most of these. Peptidases in clan CA are usually sensitive to the small molecule inhibitor E64, which is ineffective against peptidases from other clans of cysteine peptidases [PMID: 7044372].
Clan CD includes proteins with a caspase-like fold. Proteins in the clan have an alpha/beta/alpha sandwich structure. There is a catalytic dyad which occurs in the order His/Cys. The active site His occurs in a His-Gly motif and the active site Cys occurs in an Ala-Cys motif; both motifs are preceded by a block of hydrophobic residues [PMID: 9891971]. Specificity is predominantly directed towards residues that occupy the S1 binding pocket, so that caspases cleave aspartyl bonds, legumains cleave asparaginyl bonds, and gingipains cleave lysyl or arginyl bonds.
Clan CE includes proteins with an adenain-like fold. The fold consists of two subdomains with the active site between them. One domain is a bundle of helices, and the other a beta barrell. The subdomains are in the opposite order to those found in peptidases from clan CA, and this is reflected in the order of active site residues: His/Asn/Gln/Cys. This has prompted speculation that proteins in clans CA and CE are related, and that members of one clan are derived from a circular permutation of the structure of the other.
Clan CL includes proteins with a sortase B-like fold. Peptidases in the clan hydrolyse and transfer bacterial cell wall peptides. The fold shows a closed beta barrel decorated with helices with the active site at one end of the barrel [PMID: 14725770]. The active site consists of a His/Cys catalytic dyad.
Cysteine peptidases with a chymotrypsin-like fold are included in clan PA, which also includes serine peptidases. Cysteine peptidases that are N-terminal nucleophile hydrolases are included in clan PB. Cysteine peptidases with a tertiary structure similar to that of the serine-type aspartyl dipeptidase are included in clan PC. Cysteine peptidases with an intein-like fold are included in clan PD, which also includes asparagine lyases.