Cathepsin D
Cathepsin D is a protein that in humans is encoded by the CTSD gene.[1][2]
This gene encodes a lysosomal aspartyl protease composed of a dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. This proteinase, which is a member of the peptidase A1 family, has a specificity similar to but narrower than that of pepsin A. Transcription of this gene is initiated from several sites, including one which is a start site for an estrogen-regulated transcript. Mutations in this gene are involved in the pathogenesis of several diseases, including breast cancer and possibly Alzheimer disease.[2]
It has been used as a breast cancer tumor marker.[3]
Cathepsin-D is an aspartic protease that depends critically on protonation of its active site Asp residue and gets activated at pH 5 in endosome of hepatocytes where it degrades insulin. Along with Asp-protonation, lower pH also leads to conformational switch in cathepsin-D : the N terminal segment of the protease moves out of the active site as pH drops [4] [5] [6] .
References
- ^ Faust PL, Kornfeld S, Chirgwin JM (Sep 1985). "Cloning and sequence analysis of cDNA for human cathepsin D". Proc Natl Acad Sci U S A 82 (15): 4910–4. doi:10.1073/pnas.82.15.4910. PMC 390467. PMID 3927292. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=390467.
- ^ a b "Entrez Gene: CTSD cathepsin D". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1509.
- ^ Wolf M, Clark-Lewis I, Buri C, Langen H, Lis M, Mazzucchelli L (April 2003). "Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer". Am. J. Pathol. 162 (4): 1183–90. PMC 1851240. PMID 12651610. http://ajp.amjpathol.org/cgi/pmidlookup?view=long&pmid=12651610.
- ^ Authier F, Métioui M, Fabrega S, Kouach M, Briand G (2002). "Endosomal proteolysis of internalized insulin at the C-terminal region of the B chain by cathepsin D". J. Biol. Chem. 277 (11): 9437–9446. doi:10.1074/jbc.M110188200. PMID 11779865.
- ^ Lee Angela, Gulnik Sergei, Erickson John (1998). "Conformational switching in an aspartic proteinase". Nat.Struct.Mol.Biol. 5: 866–871. doi:10.1038/2306.
- ^ Petsko Gregory, Ringe Dagmar (2004). Protein Structure and Function. ISBN 9781405119221. http://books.google.com/?id=2yRDWkHhN9QC&printsec=frontcover&dq=protein+structure+function+petsko#v=onepage&q=&f=false.
External links
Further reading
- Chao J, Miao RQ, Chen V, et al. (2001). "Novel roles of kallistatin, a specific tissue kallikrein inhibitor, in vascular remodeling.". Biol. Chem. 382 (1): 15–21. doi:10.1515/BC.2001.003. PMID 11258665.
- Leto G, Tumminello FM, Crescimanno M, et al. (2004). "Cathepsin D expression levels in nongynecological solid tumors: clinical and therapeutic implications.". Clin. Exp. Metastasis 21 (2): 91–106. doi:10.1023/B:CLIN.0000024740.44602.b7. PMID 15168727.
- Liaudet-Coopman E, Beaujouin M, Derocq D, et al. (2006). "Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis.". Cancer Lett. 237 (2): 167–79. doi:10.1016/j.canlet.2005.06.007. PMID 16046058.
- Knight CG, Barrett AJ (1976). "Interaction of human cathepsin D with the inhibitor pepstatin.". Biochem. J. 155 (1): 117–25. PMC 1172808. PMID 938470. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1172808.
- Gulnik S, Baldwin ET, Tarasova N, Erickson J (1992). "Human liver cathepsin D. Purification, crystallization and preliminary X-ray diffraction analysis of a lysosomal enzyme.". J. Mol. Biol. 227 (1): 265–70. doi:10.1016/0022-2836(92)90696-H. PMID 1522590.
- Conner GE, Richo G (1992). "Isolation and characterization of a stable activation intermediate of the lysosomal aspartyl protease cathepsin D.". Biochemistry 31 (4): 1142–7. doi:10.1021/bi00119a024. PMID 1734961.
- Fujita H, Tanaka Y, Noguchi Y, et al. (1991). "Isolation and sequencing of a cDNA clone encoding rat liver lysosomal cathepsin D and the structure of three forms of mature enzymes.". Biochem. Biophys. Res. Commun. 179 (1): 190–6. doi:10.1016/0006-291X(91)91353-E. PMID 1883350.
- Dunn AD, Crutchfield HE, Dunn JT (1991). "Thyroglobulin processing by thyroidal proteases. Major sites of cleavage by cathepsins B, D, and L.". J. Biol. Chem. 266 (30): 20198–204. PMID 1939080.
- Lenarcic B, Krasovec M, Ritonja A, et al. (1991). "Inactivation of human cystatin C and kininogen by human cathepsin D.". FEBS Lett. 280 (2): 211–5. doi:10.1016/0014-5793(91)80295-E. PMID 2013314.
- Redecker B, Heckendorf B, Grosch HW, et al. (1991). "Molecular organization of the human cathepsin D gene.". DNA Cell Biol. 10 (6): 423–31. doi:10.1089/dna.1991.10.423. PMID 2069717.
- Conner GE, Udey JA (1990). "Expression and refolding of recombinant human fibroblast procathepsin D.". DNA Cell Biol. 9 (1): 1–9. doi:10.1089/dna.1990.9.1. PMID 2180427.
- Capony F, Rougeot C, Montcourrier P, et al. (1989). "Increased secretion, altered processing, and glycosylation of pro-cathepsin D in human mammary cancer cells.". Cancer Res. 49 (14): 3904–9. PMID 2736531.
- Lenarcic B, Kos J, Dolenc I, et al. (1988). "Cathepsin D inactivates cysteine proteinase inhibitors, cystatins.". Biochem. Biophys. Res. Commun. 154 (2): 765–72. doi:10.1016/0006-291X(88)90206-9. PMID 3261170.
- Westley BR, May FE (1987). "Oestrogen regulates cathepsin D mRNA levels in oestrogen responsive human breast cancer cells.". Nucleic Acids Res. 15 (9): 3773–86. doi:10.1093/nar/15.9.3773. PMC 340781. PMID 3588310. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=340781.
- Terayama H, Fukuzumi R (1987). "Ubiquitous presence of calciferin-like and cathepsin D-like activities in the sera (vertebrates) and humoral fluids (invertebrates).". Comp. Biochem. Physiol., B 87 (4): 675–9. doi:10.1016/0305-0491(87)90373-7. PMID 3665421.
- Sekiguchi K, Siri A, Zardi L, Hakomori S (1985). "Differences in domain structure between human fibronectins isolated from plasma and from culture supernatants of normal and transformed fibroblasts. Studies with domain-specific antibodies.". J. Biol. Chem. 260 (8): 5105–14. PMID 3988746.
- Lemansky P, Gieselmann V, Hasilik A, von Figura K (1984). "Cathepsin D and beta-hexosaminidase synthesized in the presence of 1-deoxynojirimycin accumulate in the endoplasmic reticulum.". J. Biol. Chem. 259 (16): 10129–35. PMID 6236213.
- Dreyer RN, Bausch KM, Fracasso P, et al. (1994). "Processing of the pre-beta-amyloid protein by cathepsin D is enhanced by a familial Alzheimer's disease mutation.". Eur. J. Biochem. 224 (2): 265–71. doi:10.1111/j.1432-1033.1994.00265.x. PMID 7523115.
- Atkins KB, Troen BR (1995). "Regulation of cathepsin D gene expression in HL-60 cells by retinoic acid and calcitriol.". Cell Growth Differ. 6 (7): 871–7. PMID 7547509.
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1lya: CRYSTAL STRUCTURES OF NATIVE AND INHIBITED FORMS OF HUMAN CATHEPSIN D: IMPLICATIONS FOR LYSOSOMAL TARGETING AND DRUG DESIGN
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1lyb: CRYSTAL STRUCTURES OF NATIVE AND INHIBITED FORMS OF HUMAN CATHEPSIN D: IMPLICATIONS FOR LYSOSOMAL TARGETING AND DRUG DESIGN
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1lyw: CATHEPSIN D AT PH 7.5
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