Cathepsin D is a protein that in humans is encoded by the CTSDgene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathepsin D is an aspartic endo-protease that is ubiquitously distributed in lysosomes. The main function of cathepsin D is to degrade proteins and activate precursors of bioactive proteins in pre-lysosomal compartments. 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 the CTSD gene is initiated from several sites, including one that 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. Homozygous deletion of the CTSD gene leads to early lethality in the post-natal phase. Deficiency of CTSD gene has been reported an underlying cause of neuronal ceroid lipofuscinosis (NCL).
The catalytic sites of cathepsin D include two critical aspartic residues (amino acid 33 and 231) located on the 14 kDa and 34kDa chains. The ultimate form of mature cathepsin D is composed of 337 amino acid residues, 196 amino acid residues in the heavy chain and 141 in the light chain. These two chains are linked by the hydrophobic effect.
The optimum pH for cathepsin D in vitro is 4.5-5.0. Cathepsin-D is an aspartic protease that depends critically on protonation of its active site Asp residue. 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. Similar to other aspartic protainases, cathepsin D accommodates up to 8 amino acid residues in the binding cleft of the active site. The main physiological functions of cathepsin D consist of metabolic degradation of intracellular proteins, activation and degradation of polypeptidehormones and growth factors, activation of enzymatic precursors, processing of enzyme activators and inhibitors, brain antigen processing and regulation of programmed cell death.
The NCLs present with progressive loss of visual function and neurodevelopmental decline, seizure, myoclonic jerks and premature death. The CTSD gene is one of the identified eight genes the deficiency of which is responsible for NCLs. It has been reported that a homozygous single nucleotide duplication in exon 6 could alter the reading frame and causes a premature stop codon at position 255. Over-expression of cathepsin D stimulates tumorigenicity and metastasis as well as initiation of tumor apoptosis. This protease has been regarded an independent marker of poor prognosis in breast cancer being correlated with the incidence of clinical metastasis. Knock-out of CTSD gene would cause intestinal necrosis and hemorrhage and increase apoptosis in thymus, indicating that cathepsin D is required in certain epithelial cells for tissue remodeling and renewal. It is also reported that there might be a strong effect for CTSD genotype on Alzheimer disease risk in male. Cathepsin D enzymatic activity induces hydrolytic modification of apolipoprotein B-100-containing lipoproteins, including LDL, which means it may be involved in atherosclerosis as well.
^Diment S, Martin KJ, Stahl PD (August 1989). "Cleavage of parathyroid hormone in macrophage endosomes illustrates a novel pathway for intracellular processing of proteins". The Journal of Biological Chemistry. 264 (23): 13403–6. PMID2760027.
^Minarowska A, Gacko M, Karwowska A, Minarowski Ł (2008). "Human cathepsin D". Folia Histochemica Et Cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society. 46 (1): 23–38. doi:10.2478/v10042-008-0003-x. PMID18296260.
^Briozzo P, Morisset M, Capony F, Rougeot C, Rochefort H (July 1988). "In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells". Cancer Research. 48 (13): 3688–92. PMID3378211.
^Authier F, Metioui M, Fabrega S, Kouach M, Briand G (March 2002). "Endosomal proteolysis of internalized insulin at the C-terminal region of the B chain by cathepsin D". The Journal of Biological Chemistry. 277 (11): 9437–46. doi:10.1074/jbc.M110188200. PMID11779865.
^Baechle D, Flad T, Cansier A, Steffen H, Schittek B, Tolson J, Herrmann T, Dihazi H, Beck A, Mueller GA, Mueller M, Stevanovic S, Garbe C, Mueller CA, Kalbacher H (March 2006). "Cathepsin D is present in human eccrine sweat and involved in the postsecretory processing of the antimicrobial peptide DCD-1L". The Journal of Biological Chemistry. 281 (9): 5406–15. doi:10.1074/jbc.M504670200. PMID16354654.
^ abHakala JK, Oksjoki R, Laine P, Du H, Grabowski GA, Kovanen PT, Pentikäinen MO (August 2003). "Lysosomal enzymes are released from cultured human macrophages, hydrolyze LDL in vitro, and are present extracellularly in human atherosclerotic lesions". Arteriosclerosis, Thrombosis, and Vascular Biology. 23 (8): 1430–6. doi:10.1161/01.ATV.0000077207.49221.06. PMID12750117.
^Bańkowska A, Gacko M, Chyczewska E, Worowska A (1997). "Biological and diagnostic role of cathepsin D". Roczniki Akademii Medycznej W Białymstoku. 42 Suppl 1: 79–85. PMID9337526.
^Traynor JP, Oun HA, McKenzie P, Shilliday IR, McKay IG, Dunlop A, Geddes CC, Mactier RA (November 2005). "Assessing the utility of the stop dialysate flow method in patients receiving haemodiafiltration". Nephrology, Dialysis, Transplantation. 20 (11): 2479–84. doi:10.1093/ndt/gfi021. PMID16046508.
^Menzer G, Müller-Thomsen T, Meins W, Alberici A, Binetti G, Hock C, Nitsch RM, Stoppe G, Reiss J, Finckh U (March 2001). "Non-replication of association between cathepsin D genotype and late onset Alzheimer disease". American Journal of Medical Genetics. 105 (2): 179–82. doi:10.1002/ajmg.1204. PMID11304834.
^Haidar B, Kiss RS, Sarov-Blat L, Brunet R, Harder C, McPherson R, Marcel YL (December 2006). "Cathepsin D, a lysosomal protease, regulates ABCA1-mediated lipid efflux". The Journal of Biological Chemistry. 281 (52): 39971–81. doi:10.1074/jbc.M605095200. PMID17032648.
^Umezawa H, Aoyagi T, Morishima H, Matsuzaki M, Hamada M (May 1970). "Pepstatin, a new pepsin inhibitor produced by Actinomycetes". The Journal of Antibiotics. 23 (5): 259–62. doi:10.7164/antibiotics.23.259. PMID4912600.
^Kim SJ, Kim KH, Ahn ER, Yoo BC, Kim SY (January 2013). "Depletion of cathepsin D by transglutaminase 2 through protein cross-linking promotes cell survival". Amino Acids. 44 (1): 73–80. doi:10.1007/s00726-011-1089-6. PMID21960143.
^Devosse T, Dutoit R, Migeotte I, De Nadai P, Imbault V, Communi D, Salmon I, Parmentier M (August 2011). "Processing of HEBP1 by cathepsin D gives rise to F2L, the agonist of formyl peptide receptor 3". Journal of Immunology. 187 (3): 1475–85. doi:10.4049/jimmunol.1003545. PMID21709160.
^Mariani E, Seripa D, Ingegni T, Nocentini G, Mangialasche F, Ercolani S, Cherubini A, Metastasio A, Pilotto A, Senin U, Mecocci P (September 2006). "Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease". Journal of the Neurological Sciences. 247 (2): 187–91. doi:10.1016/j.jns.2006.05.043. PMID16784755.
Gulnik S, Baldwin ET, Tarasova N, Erickson J (September 1992). "Human liver cathepsin D. Purification, crystallization and preliminary X-ray diffraction analysis of a lysosomal enzyme". Journal of Molecular Biology. 227 (1): 265–70. doi:10.1016/0022-2836(92)90696-H. PMID1522590.
Conner GE, Richo G (February 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. PMID1734961.
Fujita H, Tanaka Y, Noguchi Y, Kono A, Himeno M, Kato K (August 1991). "Isolation and sequencing of a cDNA clone encoding rat liver lysosomal cathepsin D and the structure of three forms of mature enzymes". Biochemical and Biophysical Research Communications. 179 (1): 190–6. doi:10.1016/0006-291X(91)91353-E. PMID1883350.
Dunn AD, Crutchfield HE, Dunn JT (October 1991). "Thyroglobulin processing by thyroidal proteases. Major sites of cleavage by cathepsins B, D, and L". The Journal of Biological Chemistry. 266 (30): 20198–204. PMID1939080.
Lenarcic B, Krasovec M, Ritonja A, Olafsson I, Turk V (March 1991). "Inactivation of human cystatin C and kininogen by human cathepsin D". FEBS Letters. 280 (2): 211–5. doi:10.1016/0014-5793(91)80295-E. PMID2013314.
Redecker B, Heckendorf B, Grosch HW, Mersmann G, Hasilik A (1991). "Molecular organization of the human cathepsin D gene". DNA and Cell Biology. 10 (6): 423–31. doi:10.1089/dna.1991.10.423. PMID2069717.
Conner GE, Udey JA (1990). "Expression and refolding of recombinant human fibroblast procathepsin D". DNA and Cell Biology. 9 (1): 1–9. doi:10.1089/dna.1990.9.1. PMID2180427.
Capony F, Rougeot C, Montcourrier P, Cavailles V, Salazar G, Rochefort H (July 1989). "Increased secretion, altered processing, and glycosylation of pro-cathepsin D in human mammary cancer cells". Cancer Research. 49 (14): 3904–9. PMID2736531.
Lenarcic B, Kos J, Dolenc I, Lucovnik P, Krizaj I, Turk V (July 1988). "Cathepsin D inactivates cysteine proteinase inhibitors, cystatins". Biochemical and Biophysical Research Communications. 154 (2): 765–72. doi:10.1016/0006-291X(88)90206-9. PMID3261170.
Terayama H, Fukuzumi R (1987). "Ubiquitous presence of calciferin-like and cathepsin D-like activities in the sera (vertebrates) and humoral fluids (invertebrates)". Comparative Biochemistry and Physiology. B, Comparative Biochemistry. 87 (4): 675–9. doi:10.1016/0305-0491(87)90373-7. PMID3665421.
Sekiguchi K, Siri A, Zardi L, Hakomori S (April 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". The Journal of Biological Chemistry. 260 (8): 5105–14. PMID3988746.
Lemansky P, Gieselmann V, Hasilik A, von Figura K (August 1984). "Cathepsin D and beta-hexosaminidase synthesized in the presence of 1-deoxynojirimycin accumulate in the endoplasmic reticulum". The Journal of Biological Chemistry. 259 (16): 10129–35. PMID6236213.
Dreyer RN, Bausch KM, Fracasso P, Hammond LJ, Wunderlich D, Wirak DO, Davis G, Brini CM, Buckholz TM, König G (September 1994). "Processing of the pre-beta-amyloid protein by cathepsin D is enhanced by a familial Alzheimer's disease mutation". European Journal of Biochemistry / FEBS. 224 (2): 265–71. doi:10.1111/j.1432-1033.1994.00265.x. PMID7523115.
Atkins KB, Troen BR (July 1995). "Regulation of cathepsin D gene expression in HL-60 cells by retinoic acid and calcitriol". Cell Growth & Differentiation. 6 (7): 871–7. PMID7547509.