Cathepsin D

CTSD
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1LYA, 1LYB, 1LYW, 4OBZ, 4OC6, 4OD9
Identifiers
Aliases	CTSD , CLN10, CPSD, HEL-S-130P, cathepsin D
External IDs	OMIM: 116840; MGI: 88562; HomoloGene: 55616; GeneCards: CTSD; OMA:CTSD - orthologs
Gene location (Human) Chr. Chromosome 11 (human) [1] Band 11p15.5 Start 1,752,752 bp [1] End 1,764,573 bp [1]
Gene location (Mouse) Chr. Chromosome 7 (mouse) [2] Band 7|7 F5 Start 141,929,648 bp [2] End 141,941,775 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right adrenal cortex left adrenal gland left adrenal cortex apex of heart stromal cell of endometrium right lung granulocyte upper lobe of left lung gallbladder olfactory zone of nasal mucosa Top expressed in choroid plexus of fourth ventricle stroma of bone marrow calvaria granulocyte transitional epithelium of urinary bladder lip esophagus muscle of thigh retinal pigment epithelium mesenteric lymph nodes More reference expression data BioGPS More reference expression data
Gene ontology Molecular function peptidase activity hydrolase activity protein binding serine-type endopeptidase activity cysteine-type endopeptidase activity aspartic-type endopeptidase activity aspartic-type peptidase activity Cellular component lysosomal lumen extracellular exosome membrane raft extracellular matrix lysosome melanosome extracellular space specific granule lumen tertiary granule lumen ficolin-1-rich granule lumen extracellular region collagen-containing extracellular matrix lysosomal membrane endosome membrane Biological process protein catabolic process autophagy collagen catabolic process antigen processing and presentation of exogenous peptide antigen via MHC class II proteolysis neutrophil degranulation lipoprotein catabolic process positive regulation of apoptotic process positive regulation of cysteine-type endopeptidase activity involved in apoptotic process regulation of establishment of protein localization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1509 13033 Ensembl ENSG00000117984 ENSMUSG00000007891 UniProt P07339 P18242 RefSeq (mRNA) NM_001909 NM_009983 RefSeq (protein) NP_001900 NP_034113 Location (UCSC) Chr 11: 1.75 – 1.76 Mb Chr 7: 141.93 – 141.94 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cathepsin D is a protein that in humans is encoded by the CTSD gene. ^{[5] [6]} 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. ^[7] The main function of cathepsin D is to degrade proteins and activate precursors of bioactive proteins in pre-lysosomal compartments. ^[8] 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. ^[6] Homozygous deletion of the CTSD gene leads to early lethality in the postnatal phase. ^[9] Deficiency of CTSD gene has been reported an underlying cause of neuronal ceroid lipofuscinosis (NCL). ^[10]

Structure

Gene

The CTSD gene is located at chromosome 11.

Protein

The catalytic sites of cathepsin D include two critical aspartic residues (amino acid 33 and 231) located on the 14 kDa and 34kDa chains. ^[11] 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. ^[12]

Function

The optimum pH for cathepsin D in vitro is 4.5-5.0. ^[13] 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. ^{[14] [15] [16]} 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. ^{[17] [18] [19] [20]} Cathepsin D can also be found in the extracellular space ^[20] and it is one of the few cathepsins, that shows some activity at neutral pH. ^[21] It is able to activate the growth factors VEGF-C and VEGF-D, which might partly explain its relevance for tumor progression. ^[22]

Clinical significance

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. ^[10] 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. ^{[23] [24]} 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. ^[9] It is also reported that there might be a strong effect for CTSD genotype on Alzheimer disease risk in male. ^[25] 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. ^{[18] [26]}

Interaction

• Pepstatin ^[27]
• Transglutaminase 2 ^[28]
• HEBP1 ^[29]
• A2M ^[30]
• Ceramide ^[31]

References

1. GRCh38: Ensembl release 89: ENSG00000117984 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000007891 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Faust PL, Kornfeld S, Chirgwin JM (August 1985). "Cloning and sequence analysis of cDNA for human cathepsin D". Proceedings of the National Academy of Sciences of the United States of America. 82 (15): 4910–4914. Bibcode:1985PNAS...82.4910F. doi: 10.1073/pnas.82.15.4910 . PMC   390467 . PMID   3927292.
6. "Entrez Gene: CTSD cathepsin D".
7. Barrett AJ (April 1970). "Cathepsin D. Purification of isoenzymes from human and chicken liver". The Biochemical Journal. 117 (3): 601–607. doi:10.1042/bj1170601. PMC   1178965 . PMID   5419752.
8. 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): 13403–13406. doi: 10.1016/S0021-9258(18)80010-2 . PMID   2760027.
9. Saftig P, Hetman M, Schmahl W, Weber K, Heine L, Mossmann H, et al. (August 1995). "Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells". The EMBO Journal. 14 (15): 3599–3608. doi:10.1002/j.1460-2075.1995.tb00029.x. PMC   394433 . PMID   7641679.
10. Ramirez-Montealegre D, Rothberg PG, Pearce DA (June 2006). "Another disorder finds its gene". Brain. 129 (Pt 6): 1353–1356. doi: 10.1093/brain/awl132 . PMID   16738059.
11. Metcalf P, Fusek M (April 1993). "Two crystal structures for cathepsin D: the lysosomal targeting signal and active site". The EMBO Journal. 12 (4): 1293–1302. doi:10.1002/j.1460-2075.1993.tb05774.x. PMC   413340 . PMID   8467789.
12. Minarowska A, Gacko M, Karwowska A, Minarowski Ł (2008). "Human cathepsin D". Folia Histochemica et Cytobiologica. 46 (1): 23–38. doi: 10.2478/v10042-008-0003-x . PMID   18296260.
13. 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): 3688–3692. PMID   3378211.
14. 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): 9437–9446. doi: 10.1074/jbc.M110188200 . PMID   11779865.
15. Lee AY, Gulnik SV, Erickson JW (October 1998). "Conformational switching in an aspartic proteinase". Nature Structural Biology. 5 (10): 866–871. doi:10.1038/2306. PMID   9783744. S2CID   5685201.
16. Petsko G, Ringe D (2004). Protein Structure and Function. Oxford [England]; Sunderland, MA; New York: Oxford University Press. ISBN   978-1-4051-1922-1.
17. Baechle D, Flad T, Cansier A, Steffen H, Schittek B, Tolson J, et al. (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): 5406–5415. doi: 10.1074/jbc.M504670200 . PMID   16354654.
18. Hakala JK, Oksjoki R, Laine P, Du H, Grabowski GA, Kovanen PT, et al. (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): 1430–1436. doi: 10.1161/01.ATV.0000077207.49221.06 . PMID   12750117.
19. Bańkowska A, Gacko M, Chyczewska E, Worowska A (1997). "Biological and diagnostic role of cathepsin D". Roczniki Akademii Medycznej W Bialymstoku. 42 (Suppl 1): 79–85. PMID   9337526.
20. Benes P, Vetvicka V, Fusek M (October 2008). "Cathepsin D—many functions of one aspartic protease". Critical Reviews in Oncology/Hematology. 68 (1): 12–28. doi:10.1016/j.critrevonc.2008.02.008. PMC   2635020 . PMID   18396408.
21. Lkhider M, Castino R, Bouguyon E, Isidoro C, Ollivier-Bousquet M (October 2004). "Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions". Journal of Cell Science. 117 (Pt 21): 5155–5164. doi: 10.1242/jcs.01396 . PMID   15456852.
22. Jha SK, Rauniyar K, Chronowska E, Mattonet K, Maina EW, Koistinen H, et al. (2019-05-17). "KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D". eLife. 8 e44478: –44478. doi: 10.7554/eLife.44478 . ISSN   2050-084X. PMC   6588350 . PMID   31099754.
23. Traynor JP, Oun HA, McKenzie P, Shilliday IR, McKay IG, Dunlop A, et al. (November 2005). "Assessing the utility of the stop dialysate flow method in patients receiving haemodiafiltration". Nephrology, Dialysis, Transplantation. 20 (11): 2479–2484. doi: 10.1093/ndt/gfi021 . PMID   16046508.
24. 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". The American Journal of Pathology. 162 (4): 1183–1190. doi:10.1016/S0002-9440(10)63914-4. PMC   1851240 . PMID   12651610.
25. Menzer G, Müller-Thomsen T, Meins W, Alberici A, Binetti G, Hock C, et al. (March 2001). "Non-replication of association between cathepsin D genotype and late onset Alzheimer disease". American Journal of Medical Genetics. 105 (2): 179–182. doi:10.1002/ajmg.1204. PMID   11304834.
26. Haidar B, Kiss RS, Sarov-Blat L, Brunet R, Harder C, McPherson R, et al. (December 2006). "Cathepsin D, a lysosomal protease, regulates ABCA1-mediated lipid efflux". The Journal of Biological Chemistry. 281 (52): 39971–39981. doi: 10.1074/jbc.M605095200 . PMID   17032648.
27. 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): 259–262. doi: 10.7164/antibiotics.23.259 . PMID   4912600.
28. 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. PMID   21960143. S2CID   17149825.
29. Devosse T, Dutoit R, Migeotte I, De Nadai P, Imbault V, Communi D, et al. (August 2011). "Processing of HEBP1 by cathepsin D gives rise to F2L, the agonist of formyl peptide receptor 3". Journal of Immunology. 187 (3). Baltimore, Md.: 1475–1485. doi: 10.4049/jimmunol.1003545 . hdl: 2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/114502 . PMID   21709160.
30. Mariani E, Seripa D, Ingegni T, Nocentini G, Mangialasche F, Ercolani S, et al. (September 2006). "Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease". Journal of the Neurological Sciences. 247 (2): 187–191. doi:10.1016/j.jns.2006.05.043. PMID   16784755. S2CID   34224448.
31. Heinrich M, Wickel M, Schneider-Brachert W, Sandberg C, Gahr J, Schwandner R, et al. (October 1999). "Cathepsin D targeted by acid sphingomyelinase-derived ceramide". The EMBO Journal. 18 (19): 5252–5263. doi:10.1093/emboj/18.19.5252. PMC   1171596 . PMID   10508159.

Further reading

• Chao J, Miao RQ, Chen V, Chen LM, Chao L (January 2001). "Novel roles of kallistatin, a specific tissue kallikrein inhibitor, in vascular remodeling". Biological Chemistry. 382 (1): 15–21. doi:10.1515/BC.2001.003. PMID   11258665. S2CID   33204682.
• Leto G, Tumminello FM, Crescimanno M, Flandina C, Gebbia N (2004). "Cathepsin D expression levels in nongynecological solid tumors: clinical and therapeutic implications". Clinical & Experimental Metastasis. 21 (2): 91–106. doi:10.1023/B:CLIN.0000024740.44602.b7. hdl: 10447/28938 . PMID   15168727. S2CID   3476324.
• Liaudet-Coopman E, Beaujouin M, Derocq D, Garcia M, Glondu-Lassis M, Laurent-Matha V, et al. (June 2006). "Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis". Cancer Letters. 237 (2): 167–179. doi:10.1016/j.canlet.2005.06.007. PMID   16046058. S2CID   41309909.
• Knight CG, Barrett AJ (April 1976). "Interaction of human cathepsin D with the inhibitor pepstatin". The Biochemical Journal. 155 (1): 117–125. doi:10.1042/bj1550117. PMC   1172808 . PMID   938470.
• 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): 265–270. doi:10.1016/0022-2836(92)90696-H. PMID   1522590.
• Conner GE, Richo G (February 1992). "Isolation and characterization of a stable activation intermediate of the lysosomal aspartyl protease cathepsin D". Biochemistry. 31 (4): 1142–1147. doi:10.1021/bi00119a024. PMID   1734961. S2CID   3014149.
• 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): 190–196. Bibcode:1991BBRC..179..190F. doi:10.1016/0006-291X(91)91353-E. PMID   1883350.
• 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): 20198–20204. doi: 10.1016/S0021-9258(18)54909-7 . PMID   1939080.
• 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): 211–215. Bibcode:1991FEBSL.280..211L. doi: 10.1016/0014-5793(91)80295-E . PMID   2013314. S2CID   23798502.
• 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): 423–431. doi:10.1089/dna.1991.10.423. PMID   2069717.
• 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. PMID   2180427.
• 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): 3904–3909. PMID   2736531.
• 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): 765–772. Bibcode:1988BBRC..154..765L. doi:10.1016/0006-291X(88)90206-9. PMID   3261170.
• Westley BR, May FE (May 1987). "Oestrogen regulates cathepsin D mRNA levels in oestrogen responsive human breast cancer cells". Nucleic Acids Research. 15 (9): 3773–3786. doi:10.1093/nar/15.9.3773. PMC   340781 . PMID   3588310.
• 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): 675–679. doi:10.1016/0305-0491(87)90373-7. PMID   3665421.
• 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): 5105–5114. doi: 10.1016/S0021-9258(18)89185-2 . PMID   3988746.
• 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): 10129–10135. doi: 10.1016/S0021-9258(18)90939-7 . PMID   6236213.
• Dreyer RN, Bausch KM, Fracasso P, Hammond LJ, Wunderlich D, Wirak DO, et al. (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. 224 (2): 265–271. doi: 10.1111/j.1432-1033.1994.00265.x . PMID   7523115.
• 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): 871–877. PMID   7547509.

External links

• The MEROPS online database for peptidases and their inhibitors: A01.009 Archived 2008-04-02 at the Wayback Machine
• GeneReviews/NIH/NCBI/UW entry on Neuronal Ceroid-Lipofuscinoses
• PDBe-KB provides an overview of all the structure information available in the PDB for Human Cathepsin D