PROSITE documentation PDOC51124
Peptidase family C16 domain profile


Peptidase family C16 (EC 3.4.22.-) contains the coronaviruses cysteine endopeptidases involved in viral polyprotein processing [E1]. All coronaviruses encodes between one and two accessory cysteine proteinases that recognize and process one or two sites in the amino-terminal half of the replicase polyprotein during assembly of the viral replication complex. MHV, HCoV and TGEV encode two accesssory proteinases, called coronavirus papain-like proteinase 1 and 2 (PL1-PRO and PL2-PRO). IBV and SARS encodes only one called PL-PRO [1]. Coronaviruses papain-like proteinases 1 and 2 have restricted specificities, cleaving respectively two and one bond(s)in the polyprotein. This restricted activity may be due to extended specificity sites: Arg or Lys at the cleavage site position P5 are required for PL1-PRO [2], and Phe at the cleavage site position P6 is required for PL2-PRO [3]. PL1-PRO releases p28 and p65 from the N-terminus of the polyprotein; PL2-PRO cleaves between p210 and p150.

The peptidase family C16 domain is about 260 amino acids in length. This domain is predicted to have an α-β structural organisation known as the papain-like fold. It consists of three α-helices and three strands of antiparallel β-sheet [4]. The active site of the peptidase family C16 domain consists of a catalytic triad of cysteine, histidine, and aspartic acid residues [1,2,4,5,6]. The nucleophilic Cys occurs in the motif Asn-Cys-Xaa-Yaa in which Xaa is an aromatic, hydrophobic residue and Yaa is an aliphatic hydrophobic amino acid. There is little conservation around the general base His. The aspartic acid plays a significant, although not essential role, in orienting and/or stabilizing the substrate in the active site [5]. This peptidase domain also contains Cys residues involved in the formation of a zinc-binding finger which connects the left and right hand domains of a papain-like fold, and may be involved in substrate binding or control the movement of the catalytic domain [4].

Some proteins known to contain a peptidase C16 domain are listed below:

  • Murine hepatitis coronavirus (MHV) papain-like endopeptidase 2 (PLP2) (C16.006) [3,7].
  • Human coronavirus (HCoV) 229E papain-like endopeptidase 1 (C16.002) [4].
  • Murine hepatitis coronavirus (MHV) papain-like endopeptidase 1 (PLP1) (C16.001) [8].
  • Porcine epidemic diarrhea virus (PEDV) papain-like endopeptidase 1 (C16.003) [9].
  • Avian infectious bronchitis coronavirus (IBV) papain-like endopeptidase 1 (C16.005) [10].
  • SARS coronavirus papain-like endopeptidase (C16.009) [11].
Last update:

June 2022 / Text revised.


Technical section

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

PEPTIDASE_C16, PS51124; Peptidase family C16 domain profile  (MATRIX)


1AuthorsZiebuhr J. Snijder E.J. Gorbalenya A.E.
TitleVirus-encoded proteinases and proteolytic processing in the Nidovirales.
SourceJ. Gen. Virol. 81:853-879(2000).
PubMed ID10725411

2AuthorsBaker S.C. Yokomori K. Dong S. Carlisle R. Gorbalenya A.E. Koonin E.V. Lai M.M.C.
TitleIdentification of the catalytic sites of a papain-like cysteine proteinase of murine coronavirus.
SourceJ. Virol. 67:6056-6063(1993).
PubMed ID8396668

3AuthorsDong S. Baker S.C.
TitleDeterminants of the p28 cleavage site recognized by the first papain-like cysteine proteinase of murine coronavirus.
SourceVirology 204:541-549(1994).
PubMed ID12805436

4AuthorsHerold J. Siddell S.G. Gorbalenya A.E.
TitleA human RNA viral cysteine proteinase that depends upon a unique Zn2+-binding finger connecting the two domains of a papain-like fold.
SourceJ. Biol. Chem. 274:14918-14925(1999).
PubMed ID10329692

5AuthorsRatia K. Saikatendu K.S. Santarsiero B.D. Barretto N. Baker S.C. Stevens R.C. Mesecar A.D.
TitleSevere acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme.
SourceProc. Natl. Acad. Sci. U. S. A. 103:5717-5722(2006).
PubMed ID16581910

6AuthorsBarretto N. Jukneliene D. Ratia K. Chen Z. Mesecar A.D. Baker S.C.
TitleThe papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity.
SourceJ. Virol. 79:15189-15198(2005).
PubMed ID16306590

7AuthorsKanjanahaluethai A. Jukneliene D. Baker S.C.
TitleIdentification of the murine coronavirus MP1 cleavage site recognized by papain-like proteinase 2.
SourceJ. Virol. 77:7376-7382(2003).
PubMed ID12805436

8AuthorsGosert R. Kanjanahaluethai A. Egger D. Bienz K. Baker S.C.
TitleRNA replication of mouse hepatitis virus takes place at double-membrane vesicles.
SourceJ. Virol. 76:3697-3708(2002).
PubMed ID11907209

9AuthorsKocherhans R. Bridgen A. Ackermann M. Tobler K.
TitleCompletion of the porcine epidemic diarrhoea coronavirus (PEDV) genome sequence.
SourceVirus Genes 23:137-144(2001).
PubMed ID11724265

10AuthorsZiebuhr J. Thiel V. Gorbalenya A.E.
TitleThe autocatalytic release of a putative RNA virus transcription factor from its polyprotein precursor involves two paralogous papain- like proteases that cleave the same peptide bond.
SourceJ. Biol. Chem. 276:33220-33232(2001).
PubMed ID11431476

11AuthorsHarcourt B.H. Jukneliene D. Kanjanahaluethai A. Bechill J. Severson K.M. Smith C.M. Rota P.A. Baker S.C.
TitleIdentification of severe acute respiratory syndrome coronavirus replicase products and characterization of papain-like protease activity.
SourceJ. Virol. 78:13600-13612(2004).
PubMed ID15564471


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