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5  structures 78  species 2  interactions 167  sequences 6  architectures

Family: CathepsinC_exc (PF08773)

Summary: Cathepsin C exclusion domain

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Cathepsin C Edit Wikipedia article

Cathepsin C
Protein CTSC PDB 1k3b.png
PDB rendering based on 1k3b.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CTSC ; CPPI; DPP-I; DPP1; DPPI; HMS; JP; JPD; PALS; PDON1; PLS
External IDs OMIM602365 MGI109553 HomoloGene1373 ChEMBL: 2252 GeneCards: CTSC Gene
EC number 3.4.14.1
RNA expression pattern
PBB GE CTSC 201487 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1075 13032
Ensembl ENSG00000109861 ENSMUSG00000030560
UniProt P53634 P97821
RefSeq (mRNA) NM_001114173 NM_009982
RefSeq (protein) NP_001107645 NP_034112
Location (UCSC) Chr 11:
88.03 – 88.07 Mb
Chr 7:
88.28 – 88.31 Mb
PubMed search [1] [2]
Cathepsin C exclusion domain
PDB 2djg EBI.jpg
re-determination of the native structure of human dipeptidyl peptidase i (cathepsin c)
Identifiers
Symbol CathepsinC_exc
Pfam PF08773
InterPro IPR014882
SCOP 1k3b
SUPERFAMILY 1k3b

Cathepsin C (CTSC) also known as dipeptidyl peptidase I (DPP-I) is a lysosomal exo-cysteine protease belonging to the peptidase C1 family. In humans, it is encoded by the CTSC gene.[1][2]

Function

Cathepsin C appears to be a central coordinator for activation of many serine proteases in immune/inflammatory cells.

Cathepsin C catalyses excision of dipeptides from the N-terminus of protein and peptide substrates, except if (i) the amino group of the N-terminus is blocked, (ii) the site of cleavage is on either side of a proline residue, (iii) the N-terminal residue is lysine or arginine, or (iv) the structure of the peptide or protein prevents further digestion from the N-terminus.

Structure

The cDNAs encoding rat, human, murine, bovine, dog and two Schistosome cathepsin Cs have been cloned and sequenced and show that the enzyme is highly conserved.[3] The human and rat cathepsin C cDNAs encode precursors (prepro-cathepsin C) comprising signal peptides of 24 residues, pro-regions of 205 (rat cathepsin C) or 206 (human cathepsin C) residues and catalytic domains of 233 residues which contain the catalytic residues and are 30-40% identical to the mature amino acid sequences of papain and a number of other cathepsins including cathepsins, B, H, K, L, and S.[4]

The translated prepro-cathepsin C is processed into the mature form by at least four cleavages of the polypeptide chain. The signal peptide is removed during translocation or secretion of the pro-enzyme (pro-cathepsin C) and a large N-terminal proregion fragment (also known as the exclusion domain),[5] which is retained in the mature enzyme, is separated from the catalytic domain by excision of a minor C-terminal part of the pro-region, called the activation peptide. A heavy chain of about 164 residues and a light chain of about 69 residues are generated by cleavage of the catalytic domain.

Unlike the other members of the papain family, mature cathepsin C consists of four subunits, each composed of the N-terminal proregion fragment, the heavy chain and the light chain. Both the pro-region fragment and the heavy chain are glycosylated.

Clinical significance

Defects in the encoded protein have been shown to be a cause of Papillon-Lefevre disease,[6][7] an autosomal recessive disorder characterized by palmoplantar keratosis and periodontitis.

Cathepsin C functions as a key enzyme in the activation of granule serine peptidases in inflammatory cells, such as elastase and cathepsin G in neutrophils cells and chymase and tryptase in mast cells. In many inflammatory diseases, such as Rheumatoid Arthritis, Chronic Obstructive Pulmonary Disease (COPD), Inflammatory Bowel Disease, Asthma, Sepsis and Cystic Fibrosis, a significant part of the pathogenesis is caused by increased activity of some of these inflammatory proteases. Once activated by cathepsin C, the proteases are capable of degrading various extracellular matrix components, which can lead to tissue damage and chronic inflammation.

References

  1. ^ "Entrez Gene: CTSC cathepsin C". 
  2. ^ Paris A, Strukelj B, Pungercar J, Renko M, Dolenc I, Turk V (August 1995). "Molecular cloning and sequence analysis of human preprocathepsin C". FEBS Letters 369 (2–3): 326–30. doi:10.1016/0014-5793(95)00777-7. PMID 7649281. 
  3. ^ Hola-Jamriska L, Tort JF, Dalton JP, Day SR, Fan J, Aaskov J, Brindley PJ (August 1998). "Cathepsin C from Schistosoma japonicum--cDNA encoding the preproenzyme and its phylogenetic relationships". European Journal of Biochemistry / FEBS 255 (3): 527–34. doi:10.1046/j.1432-1327.1998.2550527.x. PMID 9738890. 
  4. ^ Kominami E, Ishido K, Muno D, Sato N (July 1992). "The primary structure and tissue distribution of cathepsin C". Biological Chemistry Hoppe-Seyler 373 (7): 367–73. doi:10.1515/bchm3.1992.373.2.367. PMID 1515062. 
  5. ^ Turk, D.; Janjić, V.; Stern, I.; Podobnik, M.; Lamba, D.; Dahl, S. W.; Lauritzen, C.; Pedersen, J.; Turk, V.; Turk, B. (2001). "Structure of human dipeptidyl peptidase I (cathepsin C): Exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases". The EMBO Journal 20 (23): 6570–6582. doi:10.1093/emboj/20.23.6570. PMC 125750. PMID 11726493.  edit
  6. ^ Wani AA, Devkar N, Patole MS, Shouche YS (2006). "Description of two new cathepsin C gene mutations in patients with Papillon-Lefèvre syndrome". J. Periodontol. 77 (2): 233–7. doi:10.1902/jop.2006.050124. PMID 16460249. 
  7. ^ Meade JL, de Wynter EA, Brett P, Sharif SM, Woods CG, Markham AF, Cook GP (2006). "A family with Papillon-Lefevre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity". Blood 107 (9): 3665–3668. doi:10.1182/blood-2005-03-1140. PMID 16410452. 

Further reading

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Cathepsin C exclusion domain Provide feedback

Cathepsin C (dipeptidyl peptidase I) is the physiological activator of a group of serine proteases. This domain corresponds to the exclusion domain whose structure excludes the approach of a polypeptide apart from its termini. It forms an enclosed beta barrel structure composed from 8 anti-parallel beta strands [1]. Based on a structural comparison and interaction data, it is suggested that the exclusion domain originates from a metallo-protease inhibitor [1].

Literature references

  1. Turk D, Janjic V, Stern I, Podobnik M, Lamba D, Dahl SW, Lauritzen C, Pedersen J, Turk V, Turk B; , EMBO J. 2001;20:6570-6582.: Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases. PUBMED:11726493 EPMC:11726493


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR014882

Cathepsin C (dipeptidyl peptidase I) is the physiological activator of a group of serine proteases. This protein corresponds to the exclusion domain whose structure excludes the approach of a polypeptide apart from its termini. It forms an enclosed beta barrel structure composed from 8 anti-parallel beta strands [PUBMED:11726493]. Based on a structural comparison and interaction data, it is suggested that the exclusion domain originates from a metallo-protease inhibitor [PUBMED:11726493].

Domain organisation

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Alignments

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Representative proteomes NCBI
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(42)
RP35
(50)
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RP75
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  Seed
(10)
Full
(167)
Representative proteomes NCBI
(178)
Meta
(1)
RP15
(42)
RP35
(50)
RP55
(67)
RP75
(92)
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  Seed
(10)
Full
(167)
Representative proteomes NCBI
(178)
Meta
(1)
RP15
(42)
RP35
(50)
RP55
(67)
RP75
(92)
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

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Seed source: pdb_1k3b
Previous IDs: none
Type: Domain
Author: Mistry J
Number in seed: 10
Number in full: 167
Average length of the domain: 106.90 aa
Average identity of full alignment: 39 %
Average coverage of the sequence by the domain: 23.58 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.2 20.2
Trusted cut-off 20.8 20.5
Noise cut-off 19.1 19.7
Model length: 118
Family (HMM) version: 6
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Species distribution

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Interactions

There are 2 interactions for this family. More...

CathepsinC_exc Peptidase_C1

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the CathepsinC_exc domain has been found. There are 5 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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