Papain-like protease

Last updated

Papain cartoon.png
Papain, the family's namesake member, from Carica papaya
Identifiers
SymbolPeptidase_CA
Pfam clan CL0125
ECOD 219.1.1
MEROPS CA

Papain-like proteases (or papain-like (cysteine) peptidases; abbreviated PLP or PLCP) are a large protein family of cysteine protease enzymes that share structural and enzymatic properties with the group's namesake member, papain. They are found in all domains of life. In animals, the group is often known as cysteine cathepsins or, in older literature, lysosomal peptidases. [1] In the MEROPS protease enzyme classification system, papain-like proteases form Clan CA. [2] Papain-like proteases share a common catalytic dyad active site featuring a cysteine amino acid residue that acts as a nucleophile. [1]

Contents

The human genome encodes eleven cysteine cathepsins which have a broad range of physiological functions. [3] In some parasites papain-like proteases have roles in host invasion, such as cruzipain from Trypanosoma cruzi . [1] In plants, they are involved in host defense and in development. [4] Studies of papain-like proteases from prokaryotes have lagged their eukaryotic counterparts. [1] In cellular organisms they are synthesized as preproenzymes that are not enzymatically active until mature, and their activities are tightly regulated, often by the presence of endogenous protease inhibitors such as cystatins. [3] In many RNA viruses, including significant human pathogens such as the coronaviruses SARS-CoV and SARS-CoV-2, papain-like protease protein domains often have roles in processing of polyproteins into mature viral nonstructural proteins. [5] [6] Many papain-like proteases are considered potential drug targets. [3] [7]

Classification

The MEROPS system of protease enzyme classification defines clan CA as containing the papain-like proteases. They are thought to have a shared evolutionary origin. As of 2021, the clan contained 45 families. [2] [8]

Structure

An early (1984) X-ray crystallography structure of the mature papain enzyme. The primarily alpha-helical L-domain is shown at left, while the beta-sheet-rich R-domain is shown at right. The catalytic residues are highlighted; cysteine (oxidized in this structure) in green and histidine in blue. A conserved disulfide bond is shown in cyan. From PDB: 9PAP . 9pap papain.png
An early (1984) X-ray crystallography structure of the mature papain enzyme. The primarily alpha-helical L-domain is shown at left, while the beta-sheet-rich R-domain is shown at right. The catalytic residues are highlighted; cysteine (oxidized in this structure) in green and histidine in blue. A conserved disulfide bond is shown in cyan. From PDB: 9PAP ​.

The structure of papain was among the earliest protein structures experimentally determined by X-ray crystallography. [3] [10] [9] Many papain-like protease enzymes function as monomers, though a few, such as cathepsin C (Dipeptidyl-peptidase I), are homotetramers. The mature monomer structure is characteristically divided into two lobes or subdomains, known as the L-domain (N-terminal) and the R-domain (C-terminal), where the active site is located between them. [1] The L-domain is primarily helical while the R-domain contains beta-sheets in a beta-barrel-like shape, surrounded by a helix. [3] The enzyme substrate interacts with both domains in an extended conformation. [1] [3]

Papain-like proteases are often synthesized as preproenzymes, or enzymatically inactive precursors. A signal peptide at the N-terminus, which serves as a subcellular localization signal, is cleaved by signal peptidase to form a zymogen. Post-translational modification in the form of N-linked glycosylation also occurs in parallel. [3] The zymogen is still inactive due to the presence of a propeptide which functions as an inhibitor blocking access to the active site. The propeptide is removed by proteolysis to form the mature enzyme. [1] [3] [11]

Catalytic mechanism

Papain-like proteases have a catalytic dyad consisting of a cysteine and a histidine residue, which form an ion pair through their charged thiolate and imidazolium side chains. The negatively charged cysteine thiolate functions as a nucleophile. [1] [2] Additional neighboring residues - aspartate, asparagine, or glutamine - position the catalytic residues; [1] [2] in papain, the required catalytic residues cysteine, histidine, and aspartate are sometimes called the catalytic triad (similar to serine proteases). [11] Papain-like proteases are usually endopeptidases, but some members of the group are also, or even exclusively, exopeptidases. [1] Some viral papain-like proteases, including those of coronaviruses, can also cleave isopeptide bonds and can function as deubiquitinases. [5]

Function

Eukaryotes

Mammals

In animals, especially in mammalian biology, members of the papain-like protease family are usually referred to as cysteine cathepsins - that is, the cysteine protease members of the group of proteases known as cathepsins (which includes cysteine, serine, and aspartic proteases). In humans, there are 11 cysteine cathepsins: B, C, F, H, K, L, O, S, V, X, and W. Most cathepsins are expressed throughout the body, but some have narrower tissue distribution. [1] [3]

Human cathepsin K in complex with the covalent inhibitor odanacatib, shown in light blue with the covalently modified catalytic cysteine in green. Odanacatib was studied in clinical trials as a cathepsin K inhibitor for osteoporosis. 5tdi cathepsinK odanacatib.png
Human cathepsin K in complex with the covalent inhibitor odanacatib, shown in light blue with the covalently modified catalytic cysteine in green. Odanacatib was studied in clinical trials as a cathepsin K inhibitor for osteoporosis.

Although historically known as lysosomal proteases and studied mainly for their role in protein catabolism, cysteine cathepsins have since been identified playing major roles in a number of physiological processes and disease states. As part of normal physiological processes, they are involved in key steps of antigen presentation as part of the adaptive immune system, remodeling of the extracellular matrix, differentiation of keratinocytes, and processing of peptide hormones. [1] [3] Cysteine cathepsins have been associated with cancer and tumor progression, cardiovascular disease, autoimmune disease, and other human health conditions. [11] [13] [14] Cathepsin K has a role in bone resorption and has been studied as a drug target for osteoporosis. [15]

Parasites

A number of parasites, including helminths (parasitic worms), use papain-like proteases as mechanisms for invasion of their hosts. Examples include Toxoplasma gondii and Giardia lamblia . In many flatworms, there are very high levels of expression of cysteine cathepsins; in the liver fluke Fasciola hepatica , gene duplications have produced over 20 paralogs of a cathepsin L-like enzyme. [1] Cysteine cathepsins are also part of the normal life cycle of the unicellular parasite Leishmania , where they function as virulence factors. [16] The enzyme and potential drug target cruzipain is important for the life cycle of the parasite Trypanosoma cruzi , which causes Chagas' disease. [17]

Plants

X-ray crystallography structure of papain in complex with a cystatin protease inhibitor (orange) from the taro plant. The active site residues are highlighted (cysteine in green and histidine in blue). From PDB: 3IMA . 3ima chainAB papain cystatin.png
X-ray crystallography structure of papain in complex with a cystatin protease inhibitor (orange) from the taro plant. The active site residues are highlighted (cysteine in green and histidine in blue). From PDB: 3IMA ​.

Members of the papain-like protease family play a number of important roles in plant development, including seed germination, leaf senescence, and responding to abiotic stress. Papain-like proteases are involved in regulation of programmed cell death in plants, for example in tapetum during development of pollen. They are also important in plant immunity providing defense against pests and pathogens. [4] The relationship between plant papain-like proteases and pathogen responses - such as cystatin inhibitors - have been described as an evolutionary arms race. [19]

Some PLP family members in plants have culinary and commercial applications. The family's namesake member, papain, is a protease derived from papaya, used as a meat tenderizer. [20] Similar but less widely used plant products include bromelain from pineapple and ficin from figs. [1] [20]

Prokaryotes

Although papain-like proteases are found in all domains of life, they have been less well-studied in prokaryotes than in eukaryotes. [1] Only a few prokaryotic PLP enzymes have been characterized by X-ray crystallography or enzymatic studies, mostly from pathogenic bacteria, including streptopain from Streptococcus pyogenes ; xylellain, from the plant pathogen Xylella fastidiosa ; [21] Cwp84 from Clostridioides difficile ; [22] and Lpg2622 from Legionella pneumophila . [23]

Viruses

X-ray crystallography structure of the papain-like protease (PLPro) domain from SARS-CoV-2 non-structural protein 3. The catalytic residues are highlighted with cysteine in green and histidine in blue. The blue sphere is a bound zinc ion. From PDB: 6WZU . 6wzu sarscov2 plpro.png
X-ray crystallography structure of the papain-like protease (PLPro) domain from SARS-CoV-2 non-structural protein 3. The catalytic residues are highlighted with cysteine in green and histidine in blue. The blue sphere is a bound zinc ion. From PDB: 6WZU ​.

The papain-like protease family includes a number of protein domains that are found in large polyproteins expressed by RNA viruses. [2] Among the best studied viral PLPs are nidoviral papain-like protease domains from nidoviruses, particularly those from coronaviruses. These PLPs are responsible for several cleavage events that process a large polyprotein into viral nonstructural proteins, although they perform fewer cleavages than the 3C-like protease (also known as the main protease). [5] Coronavirus PLPs are multifunctional enzymes that can also act as deubiquitinases (cleaving the isopeptide bond to ubiquitin) and "deISGylating enzymes" with analogous activity against the ubiquitin-like protein ISG15. [5] [6] In human pathogens including SARS-CoV, MERS-CoV, and SARS-CoV-2, the PLP domain is essential for viral replication and is therefore considered a drug target for the development of antiviral drugs. [6] [7] One such experimental antiviral medication, Jun12682, is being studied as a potential treatment for COVID-19, and it is believed to work by inhibiting SARS-CoV-2 papain-like protease (PLpro). [25]

Related Research Articles

<span class="mw-page-title-main">Protease</span> Enzyme that cleaves other proteins into smaller peptides

A protease is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do this by cleaving the peptide bonds within proteins by hydrolysis, a reaction where water breaks bonds. Proteases are involved in numerous biological pathways, including digestion of ingested proteins, protein catabolism, and cell signaling.

In biology and biochemistry, protease inhibitors, or antiproteases, are molecules that inhibit the function of proteases. Many naturally occurring protease inhibitors are proteins.

<span class="mw-page-title-main">Serine protease</span> Class of enzymes

Serine proteases are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Serine proteases fall into two broad categories based on their structure: chymotrypsin-like (trypsin-like) or subtilisin-like.

<span class="mw-page-title-main">Metalloproteinase</span> Type of enzyme

A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogenesis.

<span class="mw-page-title-main">Papain</span> Widely used enzyme extracted from papayas

Papain, also known as papaya proteinase I, is a cysteine protease enzyme present in papaya and mountain papaya. It is the namesake member of the papain-like protease family.

<span class="mw-page-title-main">Cathepsin</span> Family of proteases

Cathepsins are proteases found in all animals as well as other organisms. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave. Most of the members become activated at the low pH found in lysosomes. Thus, the activity of this family lies almost entirely within those organelles. There are, however, exceptions such as cathepsin K, which works extracellularly after secretion by osteoclasts in bone resorption. Cathepsins have a vital role in mammalian cellular turnover.

<span class="mw-page-title-main">Catalytic triad</span> Set of three coordinated amino acids

A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes. An acid-base-nucleophile triad is a common motif for generating a nucleophilic residue for covalent catalysis. The residues form a charge-relay network to polarise and activate the nucleophile, which attacks the substrate, forming a covalent intermediate which is then hydrolysed to release the product and regenerate free enzyme. The nucleophile is most commonly a serine or cysteine amino acid, but occasionally threonine or even selenocysteine. The 3D structure of the enzyme brings together the triad residues in a precise orientation, even though they may be far apart in the sequence.

<span class="mw-page-title-main">Cysteine protease</span> Class of enzymes

Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad.

<span class="mw-page-title-main">Cathepsin C</span> Human protease (enzyme)

Cathepsin C (CTSC) also known as dipeptidyl peptidase I (DPP-I) is a lysosomal exo-cysteine protease belonging to the peptidase C1 protein family, a subgroup of the cysteine cathepsins. In humans, it is encoded by the CTSC gene.

<span class="mw-page-title-main">Cystatin</span> Group of endogenous cysteine proteinase inhibitors

The cystatins are a family of cysteine protease inhibitors which share a sequence homology and a common tertiary structure of an alpha helix lying on top of an anti-parallel beta sheet. The family is subdivided as described below.

<span class="mw-page-title-main">Aspartic protease</span>

Aspartic proteases are a catalytic type of protease enzymes that use an activated water molecule bound to one or more aspartate residues for catalysis of their peptide substrates. In general, they have two highly conserved aspartates in the active site and are optimally active at acidic pH. Nearly all known aspartyl proteases are inhibited by pepstatin.

<span class="mw-page-title-main">Actinidain</span> Class of enzymes

Actinidain is a type of cysteine protease enzyme found in fruits including kiwifruit, pineapple, mango, banana, figs, and papaya. This enzyme is part of the peptidase C1 family of papain-like proteases.

<span class="mw-page-title-main">Cathepsin L1</span> Protein-coding gene in the species Homo sapiens

Cathepsin L1 is a protein that in humans is encoded by the CTSL1 gene. The protein is a cysteine cathepsin, a lysosomal cysteine protease that plays a major role in intracellular protein catabolism.

<span class="mw-page-title-main">Cathepsin Z</span> Protein-coding gene in the species Homo sapiens

Cathepsin Z, also called cathepsin X or cathepsin P, is a protein that in humans is encoded by the CTSZ gene. It is a member of the cysteine cathepsin family of cysteine proteases, which has 11 members. As one of the 11 cathepsins, cathepsin Z contains distinctive features from others. Cathepsin Z has been reported involved in cancer malignancy and inflammation.

<span class="mw-page-title-main">Cathepsin F</span> Protein-coding gene in the species Homo sapiens (Humans)

Cathepsin F is a protein that in humans is encoded by the CTSF gene.

Myeloid and erythroid nuclear termination stage-specific protein (MENT) is a member of the serpin family of protease inhibitors, and participates in DNA and chromatin condensation. Alongside its ability to condense chromatin, MENT is also an effective inhibitor of the proteases cathepsin K, cathepsin L, and cathepsin V, all of which are cysteine proteases. As such, although MENT is structurally classified as a member of the serpin family, it is functionally termed a "cross-class inhibitor," as it is a cysteine rather than a serine protease inhibitor.

<span class="mw-page-title-main">Chymopapain</span> Enzyme

Chymopapain is a proteolytic enzyme isolated from the latex of papaya. It is a cysteine protease which belongs to the papain-like protease (PLCP) group. Because of its proteolytic activity, it is the main molecule in the process of chemonucleolysis, used in some procedures like the treatment of herniated lower lumbar discs in the spine by a nonsurgical method.

<span class="mw-page-title-main">3C-like protease</span> Class of enzymes

The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease, is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved sites. It is a cysteine protease and a member of the PA clan of proteases. It has a cysteine-histidine catalytic dyad at its active site and cleaves a Gln–(Ser/Ala/Gly) peptide bond.

Asparagine peptide lyase are one of the seven groups in which proteases, also termed proteolytic enzymes, peptidases, or proteinases, are classified according to their catalytic residue. The catalytic mechanism of the asparagine peptide lyases involves an asparagine residue acting as nucleophile to perform a nucleophilic elimination reaction, rather than hydrolysis, to catalyse the breaking of a peptide bond.

<span class="mw-page-title-main">Nidoviral papain-like protease</span> Papain-like protease protein domain

The nidoviral papain-like protease is a papain-like protease protein domain encoded in the genomes of nidoviruses. It is expressed as part of a large polyprotein from the ORF1a gene and has cysteine protease enzymatic activity responsible for proteolytic cleavage of some of the N-terminal viral nonstructural proteins within the polyprotein. A second protease also encoded by ORF1a, called the 3C-like protease or main protease, is responsible for the majority of further cleavages. Coronaviruses have one or two papain-like protease domains; in SARS-CoV and SARS-CoV-2, one PLPro domain is located in coronavirus nonstructural protein 3 (nsp3). Arteriviruses have two to three PLP domains. In addition to their protease activity, PLP domains function as deubiquitinating enzymes (DUBs) that can cleave the isopeptide bond found in ubiquitin chains. They are also "deISGylating" enzymes that remove the ubiquitin-like domain interferon-stimulated gene 15 (ISG15) from cellular proteins. These activities are likely responsible for antagonizing the activity of the host innate immune system. Because they are essential for viral replication, papain-like protease domains are considered drug targets for the development of antiviral drugs against human pathogens such as MERS-CoV, SARS-CoV, and SARS-CoV-2.

References

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  2. 1 2 3 4 5 "Summary for clan CA". MEROPS. Retrieved 20 December 2021.
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  9. 1 2 Kamphuis IG, Kalk KH, Swarte MB, Drenth J (October 1984). "Structure of papain refined at 1.65 A resolution". Journal of Molecular Biology. 179 (2): 233–256. doi:10.1016/0022-2836(84)90467-4. PMID   6502713.
  10. ↑ Drenth J, Jansonius JN, Koekoek R, Swen HM, Wolthers BG (June 1968). "Structure of papain". Nature. 218 (5145): 929–932. Bibcode:1968Natur.218..929D. doi:10.1038/218929a0. PMID   5681232. S2CID   4169127.
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