Biology:Cathepsin D

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An Error has occurred retrieving Wikidata item for infobox 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 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.[3] The main function of cathepsin D is to degrade proteins and activate precursors of bioactive proteins in pre-lysosomal compartments.[4] 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.[2] Homozygous deletion of the CTSD gene leads to early lethality in the postnatal phase.[5] Deficiency of CTSD gene has been reported an underlying cause of neuronal ceroid lipofuscinosis (NCL).[6]

Structure

Gene

The CTSD gene is located at chromosome 4q32.1, consisting of 8 exons.

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.[7] 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.[8]

Function

The optimum pH for cathepsin D in vitro is 4.5-5.0.[9] 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.[10][11][12] 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 polypeptide hormones and growth factors, activation of enzymatic precursors, processing of enzyme activators and inhibitors, brain antigen processing and regulation of programmed cell death.[13][14][15][16] Cathepsin D can also be found in the extracellular space[16] and it is one of the few cathepsins, that shows some activity at neutral pH.[17] It is able to activate the growth factors VEGF-C and VEGF-D, which might partly explain its relevance for tumor progression.[18]

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.[6] 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.[19][20] 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.[5] It is also reported that there might be a strong effect for CTSD genotype on Alzheimer disease risk in male.[21] 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.[14][22]

Interaction

References

  1. "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): 4910–4. August 1985. doi:10.1073/pnas.82.15.4910. PMID 3927292. 
  2. 2.0 2.1 "Entrez Gene: CTSD cathepsin D". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1509. 
  3. "Cathepsin D. Purification of isoenzymes from human and chicken liver". The Biochemical Journal 117 (3): 601–7. April 1970. doi:10.1042/bj1170601. PMID 5419752. 
  4. "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. August 1989. PMID 2760027. 
  5. 5.0 5.1 "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): 3599–608. August 1995. doi:10.1002/j.1460-2075.1995.tb00029.x. PMID 7641679. 
  6. 6.0 6.1 "Another disorder finds its gene". Brain 129 (Pt 6): 1353–6. June 2006. doi:10.1093/brain/awl132. PMID 16738059. 
  7. "Two crystal structures for cathepsin D: the lysosomal targeting signal and active site". The EMBO Journal 12 (4): 1293–302. April 1993. doi:10.1002/j.1460-2075.1993.tb05774.x. PMID 8467789. 
  8. "Human cathepsin D". Folia Histochemica et Cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society 46 (1): 23–38. 2008. doi:10.2478/v10042-008-0003-x. PMID 18296260. 
  9. "In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells". Cancer Research 48 (13): 3688–92. July 1988. PMID 3378211. 
  10. "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. March 2002. doi:10.1074/jbc.M110188200. PMID 11779865. 
  11. "Conformational switching in an aspartic proteinase". Nature Structural Biology 5 (10): 866–71. October 1998. doi:10.1038/2306. PMID 9783744. https://zenodo.org/record/1233021. 
  12. Petsko, Gregory; Ringe, Dagmar (2004). Protein Structure and Function. Oxford [England]; Sunderland, MA; New York: Oxford University Press. ISBN 978-1-4051-1922-1. https://books.google.com/books?id=2yRDWkHhN9QC&printsec=frontcover&dq=protein+structure+function+petsko#v=onepage. 
  13. "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. March 2006. doi:10.1074/jbc.M504670200. PMID 16354654. 
  14. 14.0 14.1 "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. August 2003. doi:10.1161/01.ATV.0000077207.49221.06. PMID 12750117. 
  15. "Biological and diagnostic role of cathepsin D". Roczniki Akademii Medycznej W Białymstoku 42 Suppl 1: 79–85. 1997. PMID 9337526. 
  16. 16.0 16.1 "Cathepsin D--many functions of one aspartic protease". Critical Reviews in Oncology/Hematology 68 (1): 12–28. October 2008. doi:10.1016/j.critrevonc.2008.02.008. PMID 18396408. 
  17. "Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions". Journal of Cell Science 117 (Pt 21): 5155–64. October 2004. doi:10.1242/jcs.01396. PMID 15456852. 
  18. Jha, Sawan Kumar; Rauniyar, Khushbu; Chronowska, Ewa; Mattonet, Kenny; Maina, Eunice Wairimu; Koistinen, Hannu; Stenman, Ulf-Håkan; Alitalo, Kari et al. (2019-05-17). "KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D". eLife 8: –44478. doi:10.7554/eLife.44478. ISSN 2050-084X. PMID 31099754. 
  19. "Assessing the utility of the stop dialysate flow method in patients receiving haemodiafiltration". Nephrology, Dialysis, Transplantation 20 (11): 2479–84. November 2005. doi:10.1093/ndt/gfi021. PMID 16046508. 
  20. "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): 1183–90. April 2003. doi:10.1016/S0002-9440(10)63914-4. PMID 12651610. PMC 1851240. http://ajp.amjpathol.org/cgi/pmidlookup?view=long&pmid=12651610. [August 2017| Dead link since August 2017}}">permanent dead link]
  21. "Non-replication of association between cathepsin D genotype and late onset Alzheimer disease". American Journal of Medical Genetics 105 (2): 179–82. March 2001. doi:10.1002/ajmg.1204. PMID 11304834. 
  22. "Cathepsin D, a lysosomal protease, regulates ABCA1-mediated lipid efflux". The Journal of Biological Chemistry 281 (52): 39971–81. December 2006. doi:10.1074/jbc.M605095200. PMID 17032648. 
  23. "Pepstatin, a new pepsin inhibitor produced by Actinomycetes". The Journal of Antibiotics 23 (5): 259–62. May 1970. doi:10.7164/antibiotics.23.259. PMID 4912600. 
  24. "Depletion of cathepsin D by transglutaminase 2 through protein cross-linking promotes cell survival". Amino Acids 44 (1): 73–80. January 2013. doi:10.1007/s00726-011-1089-6. PMID 21960143. 
  25. "Processing of HEBP1 by cathepsin D gives rise to F2L, the agonist of formyl peptide receptor 3". Journal of Immunology 187 (3): 1475–85. August 2011. doi:10.4049/jimmunol.1003545. PMID 21709160. 
  26. "Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease". Journal of the Neurological Sciences 247 (2): 187–91. September 2006. doi:10.1016/j.jns.2006.05.043. PMID 16784755. 
  27. "Cathepsin D targeted by acid sphingomyelinase-derived ceramide". The EMBO Journal 18 (19): 5252–63. October 1999. doi:10.1093/emboj/18.19.5252. PMID 10508159. PMC 1171596. http://emboj.embopress.org/content/18/19/5252.long. 

Further reading

External links