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词条 Cathepsin D
释义

  1. Structure

     Gene  Protein 

  2. Function

  3. Clinical significance

  4. Interaction

  5. References

  6. Further reading

  7. External links

{{Infobox_gene}}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 post-natal 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]

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.[17][18] 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.[19] 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][20]

Interaction

  • Pepstatin[21]
  • Transglutaminase 2[22]
  • HEBP1[23]
  • A2M[24]
  • Ceramide[25]

References

1. ^{{cite journal | vauthors = Faust PL, Kornfeld S, Chirgwin JM | title = Cloning and sequence analysis of cDNA for human cathepsin D | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 15 | pages = 4910–4 | date = August 1985 | pmid = 3927292 | pmc = 390467 | doi = 10.1073/pnas.82.15.4910 }}
2. ^1 {{cite web | title = Entrez Gene: CTSD cathepsin D| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1509| accessdate = }}
3. ^{{cite journal | vauthors = Barrett AJ | title = Cathepsin D. Purification of isoenzymes from human and chicken liver | journal = The Biochemical Journal | volume = 117 | issue = 3 | pages = 601–7 | date = April 1970 | pmid = 5419752 | doi=10.1042/bj1170601 | pmc=1178965}}
4. ^{{cite journal | vauthors = Diment S, Martin KJ, Stahl PD | title = Cleavage of parathyroid hormone in macrophage endosomes illustrates a novel pathway for intracellular processing of proteins | journal = The Journal of Biological Chemistry | volume = 264 | issue = 23 | pages = 13403–6 | date = August 1989 | pmid = 2760027 }}
5. ^1 {{cite journal | vauthors = Saftig P, Hetman M, Schmahl W, Weber K, Heine L, Mossmann H, Köster A, Hess B, Evers M, von Figura K | title = Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells | journal = The EMBO Journal | volume = 14 | issue = 15 | pages = 3599–608 | date = August 1995 | pmid = 7641679 | pmc=394433}}
6. ^1 {{cite journal | vauthors = Ramirez-Montealegre D, Rothberg PG, Pearce DA | title = Another disorder finds its gene | journal = Brain | volume = 129 | issue = Pt 6 | pages = 1353–6 | date = June 2006 | pmid = 16738059 | doi = 10.1093/brain/awl132 }}
7. ^{{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}}
8. ^{{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 }}
9. ^{{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 }}
10. ^{{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 }}
11. ^{{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 }}
12. ^{{cite book | author = Petsko Gregory | author2 = Ringe Dagmar | title = Protein Structure and Function | year = 2004 | url = https://books.google.com/books?id=2yRDWkHhN9QC&printsec=frontcover&dq=protein+structure+function+petsko#v=onepage&q=&f=false | isbn = 978-1-4051-1922-1 }}
13. ^{{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 | 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 }}
14. ^1 {{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 }}
15. ^{{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 Suppl 1 | pages = 79–85 | date = 1997 | pmid = 9337526 }}
16. ^{{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 | doi = 10.1016/j.critrevonc.2008.02.008 | pmc=2635020}}
17. ^{{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 }}
18. ^{{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 | url = http://ajp.amjpathol.org/cgi/pmidlookup?view=long&pmid=12651610 }}{{dead link|date=August 2017 |bot=InternetArchiveBot |fix-attempted=yes }}
19. ^{{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}}
20. ^{{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 }}
21. ^{{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}}
22. ^{{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 }}
23. ^{{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 }}
24. ^{{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 }}
25. ^{{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 = http://emboj.embopress.org/content/18/19/5252.long }}

Further reading

{{Refbegin|33em}}
  • {{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 }}
  • {{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 }}
  • {{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 | 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 }}
  • {{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 }}
  • {{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 | pmid = 1939080 | doi = }}
  • {{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 }}
  • {{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 | doi = }}
  • {{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 |authorlink4=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 | pmid = 3988746 | doi = }}
  • {{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 | pmid = 6236213 | doi = }}
  • {{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 / FEBS | volume = 224 | issue = 2 | pages = 265–71 | date = September 1994 | pmid = 7523115 | doi = 10.1111/j.1432-1033.1994.00265.x }}
  • {{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 | doi = }}
{{Refend}}

External links

  • The MEROPS online database for peptidases and their inhibitors: A01.009
  • [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ncl GeneReviews/NIH/NCBI/UW entry on Neuronal Ceroid-Lipofuscinoses]
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3 : Peptidase|EC 3.4.23|Cathepsins
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