| Structural highlights
4oem is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Related: | 4oel |
| Activity: | Dipeptidyl-peptidase I, with EC number 3.4.14.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[CATC_HUMAN] Defects in CTSC are a cause of Papillon-Lefevre syndrome (PLS) [MIM:245000]; also known as keratosis palmoplantaris with periodontopathia. PLS is an autosomal recessive disorder characterized by palmoplantar keratosis and severe periodontitis affecting deciduous and permanent dentitions and resulting in premature tooth loss. The palmoplantar keratotic phenotype vary from mild psoriasiform scaly skin to overt hyperkeratosis. Keratosis also affects other sites such as elbows and knees.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Defects in CTSC are a cause of Haim-Munk syndrome (HMS) [MIM:245010]; also known as keratosis palmoplantaris with periodontopathia and onychogryposis or Cochin Jewish disorder. HMS is an autosomal recessive disorder characterized by palmoplantar keratosis, onychogryphosis and periodontitis. Additional features are pes planus, arachnodactyly, and acroosteolysis.[13] Defects in CTSC are a cause of aggressive periodontititis type 1 (AP1) [MIM:170650]; also known as juvenile periodontitis (JPD) and prepubertal periodontitis (PPP). AP1 is characterized by severe and protracted gingival infections, leading to tooth loss. AP1 inheritance is autosomal dominant.[14] [15]
Function
[CATC_HUMAN] Thiol protease. Has dipeptidylpeptidase activity. Active against a broad range of dipeptide substrates composed of both polar and hydrophobic amino acids. Proline cannot occupy the P1 position and arginine cannot occupy the P2 position of the substrate. Can act as both an exopeptidase and endopeptidase. Activates serine proteases such as elastase, cathepsin G and granzymes A and B. Can also activate neuraminidase and factor XIII.[16]
Publication Abstract from PubMed
We examined the cathepsin C-catalyzed hydrolysis of dipeptide substrates of the form Yaa-Xaa-AMC, using steady-state and pre-steady-state kinetic methods. The substrates group into three kinetic profiles based upon the broad range observed for k(cat)/K(a) and k(cat) values, pre-steady-state time courses, and solvent kinetic isotope effects (sKIEs). The dipeptide substrate Gly-Arg-AMC displayed large values for k(cat)/K(a) (1.6 +/- 0.09 muM(-1) s(-1)) and k(cat) (255 +/- 6 s(-1)), an inverse sKIE on k(cat)/K(a) ((D)(k(cat)/K(a)) = 0.6 +/- 0.15), a modest, normal sKIE on k(cat) ((D)k(cat) = 1.6 +/- 0.2), and immeasurable pre-steady-state kinetics, indicating an extremely fast pre-steady-state rate (>400 s(-1)). (Errors on fitted values are omitted in the text for clarity but may be found in Table 2.) These results conformed to a kinetic model where the acylation (k(ac)) and deacylation (k(dac)) half-reactions are very fast and similar in value. The second substrate type, Gly-Tyr-AMC and Ser-Tyr-AMC, the latter the subject of a comprehensive kinetic study (Schneck et al. (2008) Biochemistry 47, 8697-8710), were found to be less active substrates compared to Gly-Arg-AMC, with respective k(cat)/K(a) values of 0.49 +/- 0.07 muM(-1 )s(-1) and 5.3 +/- 0.5 muM(-1 )s(-1), and k(cat) values of 28 +/- 1 s(-1) and 25 +/- 0.5 s(-1). Solvent kinetic isotope effects for Ser-Tyr-AMC were found to be inverse for k(cat)/K(a) ((D)(k(cat)/K(a)) = 0.74 +/- 0.05) and normal for k(cat) ((D)k(cat) = 2.3 +/- 0.1) but unlike Gly-Arg-AMC, pre-steady-state kinetics of Gly-Tyr-AMC and Ser-Tyr-AMC were measurable and characterized by a single-exponential burst, with fast transient rates (490 s(-1) and 390 s(-1), respectively), from which it was determined that k(ac) >> k(dac) approximately k(cat). The third substrate type, Gly-Ile-AMC, gave very low values of k(cat)/K(a) (0.0015 +/- 0.0001 muM(-1) s(-1)) and k(cat) (0.33 +/- 0.02 s(-1)), no sKIEs, ((D)(k(cat)/K(a)) = 1.05 +/- 0.5 and (D)k(cat) = 1.06 +/- 0.4), and pre-steady-state kinetics exhibited a discernible, but negligible, transient phase. For this third class of substrate, kinetic modeling was consistent with a mechanism in which k(dac) > k(ac) approximately k(cat), and for which an isotope-insensitive step in the acylation half-reaction is the slowest. The combined results of these studies suggested that the identity of the amino acid at the P(1) position of the substrate is the main determinant of catalysis. On the basis of these kinetic data, together with crystallographic studies of substrate analogues and molecular dynamics analysis with models of acyl-enzyme intermediates, we present a catalytic model derived from the relative rates of the acylation vs deacylation half-reactions of cathepsin C. The chemical steps of catalysis are proposed to be dependent upon the conformational freedom of the amino acid substituents for optimal alignment for thiolation (acylation) or hydrolysis (deacylation). These studies suggest ideas for inhibitor design for papain-family cysteine proteases and strategies to progress drug discovery for other classes of disease-relevant cysteine proteases.
The amino-acid substituents of dipeptide substrates of cathepsin C can determine the rate-limiting steps of catalysis.,Rubach JK, Cui G, Schneck JL, Taylor AN, Zhao B, Smallwood A, Nevins N, Wisnoski D, Thrall SH, Meek TD Biochemistry. 2012 Sep 25;51(38):7551-68. doi: 10.1021/bi300719b. Epub 2012 Sep, 13. PMID:22928782[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Allende LM, Garcia-Perez MA, Moreno A, Corell A, Carasol M, Martinez-Canut P, Arnaiz-Villena A. Cathepsin C gene: First compound heterozygous patient with Papillon-Lefevre syndrome and a novel symptomless mutation. Hum Mutat. 2001 Feb;17(2):152-3. PMID:11180601 doi:<152::AID-HUMU10>3.0.CO;2-# 10.1002/1098-1004(200102)17:2<152::AID-HUMU10>3.0.CO;2-#
- ↑ Allende LM, Moreno A, de Unamuno P. A genetic study of cathepsin C gene in two families with Papillon-Lefevre syndrome. Mol Genet Metab. 2003 Jun;79(2):146-8. PMID:12809647
- ↑ Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench N, Hewitt C, Moynihan L, Roberts E, Woods CG, Markham A, Wong M, Widmer R, Ghaffar KA, Pemberton M, Hussein IR, Temtamy SA, Davies R, Read AP, Sloan P, Dixon MJ, Thakker NS. Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet. 1999 Dec;23(4):421-4. PMID:10581027 doi:10.1038/70525
- ↑ Hart TC, Hart PS, Michalec MD, Zhang Y, Marazita ML, Cooper M, Yassin OM, Nusier M, Walker S. Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation. J Med Genet. 2000 Feb;37(2):95-101. PMID:10662808
- ↑ Hart PS, Zhang Y, Firatli E, Uygur C, Lotfazar M, Michalec MD, Marks JJ, Lu X, Coates BJ, Seow WK, Marshall R, Williams D, Reed JB, Wright JT, Hart TC. Identification of cathepsin C mutations in ethnically diverse papillon-Lefevre syndrome patients. J Med Genet. 2000 Dec;37(12):927-32. PMID:11106356
- ↑ Nakano A, Nomura K, Nakano H, Ono Y, LaForgia S, Pulkkinen L, Hashimoto I, Uitto J. Papillon-Lefevre syndrome: mutations and polymorphisms in the cathepsin C gene. J Invest Dermatol. 2001 Feb;116(2):339-43. PMID:11180012 doi:10.1046/j.1523-1747.2001.01244.x
- ↑ Lefevre C, Blanchet-Bardon C, Jobard F, Bouadjar B, Stalder JF, Cure S, Hoffmann A, Prud'Homme JF, Fischer J. Novel point mutations, deletions, and polymorphisms in the cathepsin C gene in nine families from Europe and North Africa with Papillon-Lefevre syndrome. J Invest Dermatol. 2001 Dec;117(6):1657-61. PMID:11886537 doi:1595
- ↑ Zhang Y, Lundgren T, Renvert S, Tatakis DN, Firatli E, Uygur C, Hart PS, Gorry MC, Marks JJ, Hart TC. Evidence of a founder effect for four cathepsin C gene mutations in Papillon-Lefevre syndrome patients. J Med Genet. 2001 Feb;38(2):96-101. PMID:11158173
- ↑ Zhang Y, Hart PS, Moretti AJ, Bouwsma OJ, Fisher EM, Dudlicek L, Pettenati MJ, Hart TC. Biochemical and mutational analyses of the cathepsin c gene (CTSC) in three North American families with Papillon Lefevre syndrome. Hum Mutat. 2002 Jul;20(1):75. PMID:12112662 doi:10.1002/humu.9040
- ↑ Hewitt C, McCormick D, Linden G, Turk D, Stern I, Wallace I, Southern L, Zhang L, Howard R, Bullon P, Wong M, Widmer R, Gaffar KA, Awawdeh L, Briggs J, Yaghmai R, Jabs EW, Hoeger P, Bleck O, Rudiger SG, Petersilka G, Battino M, Brett P, Hattab F, Al-Hamed M, Sloan P, Toomes C, Dixon M, James J, Read AP, Thakker N. The role of cathepsin C in Papillon-Lefevre syndrome, prepubertal periodontitis, and aggressive periodontitis. Hum Mutat. 2004 Mar;23(3):222-8. PMID:14974080 doi:10.1002/humu.10314
- ↑ de Haar SF, Jansen DC, Schoenmaker T, De Vree H, Everts V, Beertsen W. Loss-of-function mutations in cathepsin C in two families with Papillon-Lefevre syndrome are associated with deficiency of serine proteinases in PMNs. Hum Mutat. 2004 May;23(5):524. PMID:15108292 doi:10.1002/humu.9243
- ↑ de Haar SF, Mir M, Nguyen M, Kazemi B, Ramezani GH, Everts V, Beertsen W. Gene symbol: CTSC. Disease: Papillon-Lefevre syndrome. Hum Genet. 2005 May;116(6):545. PMID:15991336
- ↑ Hart TC, Hart PS, Michalec MD, Zhang Y, Firatli E, Van Dyke TE, Stabholz A, Zlotogorski A, Shapira L, Soskolne WA. Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in cathepsin C. J Med Genet. 2000 Feb;37(2):88-94. PMID:10662807
- ↑ Hart TC, Hart PS, Michalec MD, Zhang Y, Marazita ML, Cooper M, Yassin OM, Nusier M, Walker S. Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation. J Med Genet. 2000 Feb;37(2):95-101. PMID:10662808
- ↑ Hewitt C, McCormick D, Linden G, Turk D, Stern I, Wallace I, Southern L, Zhang L, Howard R, Bullon P, Wong M, Widmer R, Gaffar KA, Awawdeh L, Briggs J, Yaghmai R, Jabs EW, Hoeger P, Bleck O, Rudiger SG, Petersilka G, Battino M, Brett P, Hattab F, Al-Hamed M, Sloan P, Toomes C, Dixon M, James J, Read AP, Thakker N. The role of cathepsin C in Papillon-Lefevre syndrome, prepubertal periodontitis, and aggressive periodontitis. Hum Mutat. 2004 Mar;23(3):222-8. PMID:14974080 doi:10.1002/humu.10314
- ↑ McGuire MJ, Lipsky PE, Thiele DL. Purification and characterization of dipeptidyl peptidase I from human spleen. Arch Biochem Biophys. 1992 Jun;295(2):280-8. PMID:1586157
- ↑ Rubach JK, Cui G, Schneck JL, Taylor AN, Zhao B, Smallwood A, Nevins N, Wisnoski D, Thrall SH, Meek TD. The amino-acid substituents of dipeptide substrates of cathepsin C can determine the rate-limiting steps of catalysis. Biochemistry. 2012 Sep 25;51(38):7551-68. doi: 10.1021/bi300719b. Epub 2012 Sep, 13. PMID:22928782 doi:http://dx.doi.org/10.1021/bi300719b
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