cathepsin D

The CTSD gene is located at chromosome 11.

The catalytic sites of cathepsin D include two critical aspartic residues (amino acid 33 and 231) located on the 14 kDa and 34kDa chains.{{cite journal | vauthors = Metcalf P, Fusek M | title = Two crystal structures for cathepsin D: the lysosomal targeting signal and active site | journal = The EMBO Journal | volume = 12 | issue = 4 | pages = 1293–302 | date = April 1993 | pmid = 8467789 | pmc=413340| doi = 10.1002/j.1460-2075.1993.tb05774.x }} 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.{{cite journal | vauthors = Minarowska A, Gacko M, Karwowska A, Minarowski Ł | title = Human cathepsin D | journal = Folia Histochemica et Cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society | volume = 46 | issue = 1 | pages = 23–38 | date = 2008 | pmid = 18296260 | doi = 10.2478/v10042-008-0003-x | doi-access = free }}

The optimum pH for cathepsin D in vitro is 4.5-5.0.{{cite journal | vauthors = Briozzo P, Morisset M, Capony F, Rougeot C, Rochefort H | title = In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells | journal = Cancer Research | volume = 48 | issue = 13 | pages = 3688–92 | date = July 1988 | pmid = 3378211 }} 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.{{cite journal | vauthors = Authier F, Metioui M, Fabrega S, Kouach M, Briand G | title = Endosomal proteolysis of internalized insulin at the C-terminal region of the B chain by cathepsin D | journal = The Journal of Biological Chemistry | volume = 277 | issue = 11 | pages = 9437–46 | date = March 2002 | pmid = 11779865 | doi = 10.1074/jbc.M110188200 | doi-access = free }}{{cite journal | vauthors = Lee AY, Gulnik SV, Erickson JW | title = Conformational switching in an aspartic proteinase | journal = Nature Structural Biology | volume = 5 | issue = 10 | pages = 866–71 | date = October 1998 | pmid = 9783744 | doi = 10.1038/2306 | s2cid = 5685201 | url = https://zenodo.org/record/1233021 }}{{cite book | last1 = Petsko | first1 = Gregory | last2 = Ringe | first2 = Dagmar | name-list-style = vanc | title = Protein Structure and Function | year = 2004 | url = https://books.google.com/books?id=2yRDWkHhN9QC&q=protein+structure+function+petsko | location = Oxford [England]; Sunderland, MA; New York | publisher = Oxford University Press | isbn = 978-1-4051-1922-1 }} Similar to other aspartic proteases, 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 polypeptide hormones and growth factors, activation of enzymatic precursors, processing of enzyme activators and inhibitors, brain antigen processing and regulation of programmed cell death.{{cite journal | vauthors = 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 | display-authors = 6 | title = Cathepsin D is present in human eccrine sweat and involved in the postsecretory processing of the antimicrobial peptide DCD-1L | journal = The Journal of Biological Chemistry | volume = 281 | issue = 9 | pages = 5406–15 | date = March 2006 | pmid = 16354654 | doi = 10.1074/jbc.M504670200 | doi-access = free }}{{cite journal | vauthors = Hakala JK, Oksjoki R, Laine P, Du H, Grabowski GA, Kovanen PT, Pentikäinen MO | title = Lysosomal enzymes are released from cultured human macrophages, hydrolyze LDL in vitro, and are present extracellularly in human atherosclerotic lesions | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 23 | issue = 8 | pages = 1430–6 | date = August 2003 | pmid = 12750117 | doi = 10.1161/01.ATV.0000077207.49221.06 | doi-access = free }}{{cite journal | vauthors = Bańkowska A, Gacko M, Chyczewska E, Worowska A | title = Biological and diagnostic role of cathepsin D | journal = Roczniki Akademii Medycznej W Białymstoku | volume = 42 | pages = 79–85 | date = 1997 | issue = Suppl 1 | pmid = 9337526 }}{{cite journal | vauthors = Benes P, Vetvicka V, Fusek M | title = Cathepsin D—many functions of one aspartic protease | journal = Critical Reviews in Oncology/Hematology | volume = 68 | issue = 1 | pages = 12–28 | date = October 2008 | pmid = 18396408 | pmc = 2635020 | doi = 10.1016/j.critrevonc.2008.02.008 }} Cathepsin D can also be found in the extracellular space and it is one of the few cathepsins, that shows some activity at neutral pH.{{cite journal | vauthors = Lkhider M, Castino R, Bouguyon E, Isidoro C, Ollivier-Bousquet M | title = Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions | journal = Journal of Cell Science | volume = 117 | issue = Pt 21 | pages = 5155–64 | date = October 2004 | pmid = 15456852 | doi = 10.1242/jcs.01396 | doi-access = free }} It is able to activate the growth factors VEGF-C and VEGF-D, which might partly explain its relevance for tumor progression.{{Cite journal| doi = 10.7554/eLife.44478| issn = 2050-084X| volume = 8| pages = –44478| last1 = Jha| first1 = Sawan Kumar| last2 = Rauniyar| first2 = Khushbu| last3 = Chronowska| first3 = Ewa| last4 = Mattonet| first4 = Kenny| last5 = Maina| first5 = Eunice Wairimu| last6 = Koistinen| first6 = Hannu| last7 = Stenman| first7 = Ulf-Håkan| last8 = Alitalo| first8 = Kari| last9 = Jeltsch| first9 = Michael| title = KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D| journal = eLife| date = 2019-05-17| pmid = 31099754| pmc = 6588350| doi-access = free}}

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.{{cite journal | vauthors = Traynor JP, Oun HA, McKenzie P, Shilliday IR, McKay IG, Dunlop A, Geddes CC, Mactier RA | title = Assessing the utility of the stop dialysate flow method in patients receiving haemodiafiltration | journal = Nephrology, Dialysis, Transplantation | volume = 20 | issue = 11 | pages = 2479–84 | date = November 2005 | pmid = 16046508 | doi = 10.1093/ndt/gfi021 | doi-access = free }}{{cite journal | vauthors = Wolf M, Clark-Lewis I, Buri C, Langen H, Lis M, Mazzucchelli L | title = 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 | journal = The American Journal of Pathology | volume = 162 | issue = 4 | pages = 1183–90 | date = April 2003 | pmid = 12651610 | pmc = 1851240 | doi = 10.1016/S0002-9440(10)63914-4 }} 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.{{cite journal | vauthors = Menzer G, Müller-Thomsen T, Meins W, Alberici A, Binetti G, Hock C, Nitsch RM, Stoppe G, Reiss J, Finckh U | title = Non-replication of association between cathepsin D genotype and late onset Alzheimer disease | journal = American Journal of Medical Genetics | volume = 105 | issue = 2 | pages = 179–82 | date = March 2001 | pmid = 11304834 | doi=10.1002/ajmg.1204}} 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.{{cite journal | vauthors = Haidar B, Kiss RS, Sarov-Blat L, Brunet R, Harder C, McPherson R, Marcel YL | title = Cathepsin D, a lysosomal protease, regulates ABCA1-mediated lipid efflux | journal = The Journal of Biological Chemistry | volume = 281 | issue = 52 | pages = 39971–81 | date = December 2006 | pmid = 17032648 | doi = 10.1074/jbc.M605095200 | doi-access = free }}

• Pepstatin{{cite journal | vauthors = Umezawa H, Aoyagi T, Morishima H, Matsuzaki M, Hamada M | title = Pepstatin, a new pepsin inhibitor produced by Actinomycetes | journal = The Journal of Antibiotics | volume = 23 | issue = 5 | pages = 259–62 | date = May 1970 | pmid = 4912600 | doi=10.7164/antibiotics.23.259| doi-access = free }}
• Transglutaminase 2{{cite journal | vauthors = Kim SJ, Kim KH, Ahn ER, Yoo BC, Kim SY | title = Depletion of cathepsin D by transglutaminase 2 through protein cross-linking promotes cell survival | journal = Amino Acids | volume = 44 | issue = 1 | pages = 73–80 | date = January 2013 | pmid = 21960143 | doi = 10.1007/s00726-011-1089-6 | s2cid = 17149825 }}
• HEBP1{{cite journal | vauthors = Devosse T, Dutoit R, Migeotte I, De Nadai P, Imbault V, Communi D, Salmon I, Parmentier M | title = Processing of HEBP1 by cathepsin D gives rise to F2L, the agonist of formyl peptide receptor 3 | journal = Journal of Immunology | volume = 187 | issue = 3 | pages = 1475–85 | date = August 2011 | pmid = 21709160 | doi = 10.4049/jimmunol.1003545 | doi-access = free }}
• A2M{{cite journal | vauthors = Mariani E, Seripa D, Ingegni T, Nocentini G, Mangialasche F, Ercolani S, Cherubini A, Metastasio A, Pilotto A, Senin U, Mecocci P | title = Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease | journal = Journal of the Neurological Sciences | volume = 247 | issue = 2 | pages = 187–91 | date = September 2006 | pmid = 16784755 | doi = 10.1016/j.jns.2006.05.043 | s2cid = 34224448 }}
• Ceramide{{cite journal | vauthors = Heinrich M, Wickel M, Schneider-Brachert W, Sandberg C, Gahr J, Schwandner R, Weber T, Saftig P, Peters C, Brunner J, Krönke M, Schütze S | title = Cathepsin D targeted by acid sphingomyelinase-derived ceramide | journal = The EMBO Journal | volume = 18 | issue = 19 | pages = 5252–63 | date = October 1999 | pmid = 10508159 | pmc = 1171596 | doi = 10.1093/emboj/18.19.5252 | url = }}{{clear}}

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• {{cite journal | vauthors = Chao J, Miao RQ, Chen V, Chen LM, Chao L | title = Novel roles of kallistatin, a specific tissue kallikrein inhibitor, in vascular remodeling | journal = Biological Chemistry | volume = 382 | issue = 1 | pages = 15–21 | date = January 2001 | pmid = 11258665 | doi = 10.1515/BC.2001.003 | s2cid = 33204682 }}
• {{cite journal | vauthors = Leto G, Tumminello FM, Crescimanno M, Flandina C, Gebbia N | title = Cathepsin D expression levels in nongynecological solid tumors: clinical and therapeutic implications | journal = Clinical & Experimental Metastasis | volume = 21 | issue = 2 | pages = 91–106 | year = 2004 | pmid = 15168727 | doi = 10.1023/B:CLIN.0000024740.44602.b7 | s2cid = 3476324 | hdl = 10447/28938 | hdl-access = free }}
• {{cite journal | vauthors = Liaudet-Coopman E, Beaujouin M, Derocq D, Garcia M, Glondu-Lassis M, Laurent-Matha V, Prébois C, Rochefort H, Vignon F | title = Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis | journal = Cancer Letters | volume = 237 | issue = 2 | pages = 167–79 | date = June 2006 | pmid = 16046058 | doi = 10.1016/j.canlet.2005.06.007 | s2cid = 41309909 | url = http://www.hal.inserm.fr/inserm-00153729/document }}
• {{cite journal | vauthors = Knight CG, Barrett AJ | title = Interaction of human cathepsin D with the inhibitor pepstatin | journal = The Biochemical Journal | volume = 155 | issue = 1 | pages = 117–25 | date = April 1976 | pmid = 938470 | pmc = 1172808 | doi = 10.1042/bj1550117}}
• {{cite journal | vauthors = Gulnik S, Baldwin ET, Tarasova N, Erickson J | title = Human liver cathepsin D. Purification, crystallization and preliminary X-ray diffraction analysis of a lysosomal enzyme | journal = Journal of Molecular Biology | volume = 227 | issue = 1 | pages = 265–70 | date = September 1992 | pmid = 1522590 | doi = 10.1016/0022-2836(92)90696-H | url = https://zenodo.org/record/1253938 }}
• {{cite journal | vauthors = Conner GE, Richo G | title = Isolation and characterization of a stable activation intermediate of the lysosomal aspartyl protease cathepsin D | journal = Biochemistry | volume = 31 | issue = 4 | pages = 1142–7 | date = February 1992 | pmid = 1734961 | doi = 10.1021/bi00119a024 | s2cid = 3014149 }}
• {{cite journal | vauthors = Fujita H, Tanaka Y, Noguchi Y, Kono A, Himeno M, Kato K | title = Isolation and sequencing of a cDNA clone encoding rat liver lysosomal cathepsin D and the structure of three forms of mature enzymes | journal = Biochemical and Biophysical Research Communications | volume = 179 | issue = 1 | pages = 190–6 | date = August 1991 | pmid = 1883350 | doi = 10.1016/0006-291X(91)91353-E }}
• {{cite journal | vauthors = Dunn AD, Crutchfield HE, Dunn JT | title = Thyroglobulin processing by thyroidal proteases. Major sites of cleavage by cathepsins B, D, and L | journal = The Journal of Biological Chemistry | volume = 266 | issue = 30 | pages = 20198–204 | date = October 1991 | doi = 10.1016/S0021-9258(18)54909-7 | pmid = 1939080 | doi-access = free }}
• {{cite journal | vauthors = Lenarcic B, Krasovec M, Ritonja A, Olafsson I, Turk V | title = Inactivation of human cystatin C and kininogen by human cathepsin D | journal = FEBS Letters | volume = 280 | issue = 2 | pages = 211–5 | date = March 1991 | pmid = 2013314 | doi = 10.1016/0014-5793(91)80295-E | s2cid = 23798502 | doi-access = free | bibcode = 1991FEBSL.280..211L }}
• {{cite journal | vauthors = Redecker B, Heckendorf B, Grosch HW, Mersmann G, Hasilik A | title = Molecular organization of the human cathepsin D gene | journal = DNA and Cell Biology | volume = 10 | issue = 6 | pages = 423–31 | year = 1991 | pmid = 2069717 | doi = 10.1089/dna.1991.10.423 }}
• {{cite journal | vauthors = Conner GE, Udey JA | title = Expression and refolding of recombinant human fibroblast procathepsin D | journal = DNA and Cell Biology | volume = 9 | issue = 1 | pages = 1–9 | year = 1990 | pmid = 2180427 | doi = 10.1089/dna.1990.9.1 }}
• {{cite journal | vauthors = Capony F, Rougeot C, Montcourrier P, Cavailles V, Salazar G, Rochefort H | title = Increased secretion, altered processing, and glycosylation of pro-cathepsin D in human mammary cancer cells | journal = Cancer Research | volume = 49 | issue = 14 | pages = 3904–9 | date = July 1989 | pmid = 2736531 }}
• {{cite journal | vauthors = Lenarcic B, Kos J, Dolenc I, Lucovnik P, Krizaj I, Turk V | title = Cathepsin D inactivates cysteine proteinase inhibitors, cystatins | journal = Biochemical and Biophysical Research Communications | volume = 154 | issue = 2 | pages = 765–72 | date = July 1988 | pmid = 3261170 | doi = 10.1016/0006-291X(88)90206-9 }}
• {{cite journal | vauthors = Westley BR, May FE | title = Oestrogen regulates cathepsin D mRNA levels in oestrogen responsive human breast cancer cells | journal = Nucleic Acids Research | volume = 15 | issue = 9 | pages = 3773–86 | date = May 1987 | pmid = 3588310 | pmc = 340781 | doi = 10.1093/nar/15.9.3773 }}
• {{cite journal | vauthors = Terayama H, Fukuzumi R | title = Ubiquitous presence of calciferin-like and cathepsin D-like activities in the sera (vertebrates) and humoral fluids (invertebrates) | journal = Comparative Biochemistry and Physiology. B, Comparative Biochemistry | volume = 87 | issue = 4 | pages = 675–9 | year = 1987 | pmid = 3665421 | doi = 10.1016/0305-0491(87)90373-7 }}
• {{cite journal | vauthors = Sekiguchi K, Siri A, Zardi L, Hakomori S |author-link4=Sen-itiroh Hakomori| title = Differences in domain structure between human fibronectins isolated from plasma and from culture supernatants of normal and transformed fibroblasts. Studies with domain-specific antibodies | journal = The Journal of Biological Chemistry | volume = 260 | issue = 8 | pages = 5105–14 | date = April 1985 |doi=10.1016/S0021-9258(18)89185-2| pmid = 3988746 |doi-access=free}}
• {{cite journal | vauthors = Lemansky P, Gieselmann V, Hasilik A, von Figura K | title = Cathepsin D and beta-hexosaminidase synthesized in the presence of 1-deoxynojirimycin accumulate in the endoplasmic reticulum | journal = The Journal of Biological Chemistry | volume = 259 | issue = 16 | pages = 10129–35 | date = August 1984 | doi = 10.1016/S0021-9258(18)90939-7 | pmid = 6236213 | doi-access = free }}
• {{cite journal | vauthors = Dreyer RN, Bausch KM, Fracasso P, Hammond LJ, Wunderlich D, Wirak DO, Davis G, Brini CM, Buckholz TM, König G | title = Processing of the pre-beta-amyloid protein by cathepsin D is enhanced by a familial Alzheimer's disease mutation | journal = European Journal of Biochemistry | volume = 224 | issue = 2 | pages = 265–71 | date = September 1994 | pmid = 7523115 | doi = 10.1111/j.1432-1033.1994.00265.x | doi-access = free }}
• {{cite journal | vauthors = Atkins KB, Troen BR | title = Regulation of cathepsin D gene expression in HL-60 cells by retinoic acid and calcitriol | journal = Cell Growth & Differentiation | volume = 6 | issue = 7 | pages = 871–7 | date = July 1995 | pmid = 7547509 }}

{{Refend}}

• The MEROPS online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=A01.009 A01.009] {{Webarchive|url=https://web.archive.org/web/20080402133013/http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=A01.009 |date=2008-04-02 }}
• [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ncl GeneReviews/NIH/NCBI/UW entry on Neuronal Ceroid-Lipofuscinoses]
• [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P07339 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Cathepsin D

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Category:Proteases

Category:EC 3.4.23

Category:Cathepsins