Cathepsin D

Last updated
CTSD
Protein CTSD PDB 1lya.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CTSD , CLN10, CPSD, HEL-S-130P, cathepsin D
External IDs OMIM: 116840 MGI: 88562 HomoloGene: 55616 GeneCards: CTSD
Orthologs
SpeciesHumanMouse
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]

Contents

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

Related Research Articles

<span class="mw-page-title-main">Serpin</span> Superfamily of proteins with similar structures and diverse functions

Serpins are a superfamily of proteins with similar structures that were first identified for their protease inhibition activity and are found in all kingdoms of life. The acronym serpin was originally coined because the first serpins to be identified act on chymotrypsin-like serine proteases. They are notable for their unusual mechanism of action, in which they irreversibly inhibit their target protease by undergoing a large conformational change to disrupt the target's active site. This contrasts with the more common competitive mechanism for protease inhibitors that bind to and block access to the protease active site.

<span class="mw-page-title-main">Beta-secretase 2</span> Enzyme found in humans

Beta-secretase 2 is an enzyme that cleaves Glu-Val-Asn-Leu!Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein. BACE2 is a close homolog of BACE1.

<span class="mw-page-title-main">Cathepsin</span> Family of proteases

Cathepsins are proteases found in all animals as well as other organisms. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave. Most of the members become activated at the low pH found in lysosomes. Thus, the activity of this family lies almost entirely within those organelles. There are, however, exceptions such as cathepsin K, which works extracellularly after secretion by osteoclasts in bone resorption. Cathepsins have a vital role in mammalian cellular turnover.

<span class="mw-page-title-main">Cathepsin S</span> Protein-coding gene in the species Homo sapiens

Cathepsin S is a protein that in humans is encoded by the CTSS gene. Transcript variants utilizing alternative polyadenylation signals exist for this gene.

<span class="mw-page-title-main">Cathepsin K</span> Protein-coding gene in the species Homo sapiens

Cathepsin K, abbreviated CTSK, is an enzyme that in humans is encoded by the CTSK gene.

<span class="mw-page-title-main">Cathepsin C</span> Human protease (enzyme)

Cathepsin C (CTSC) also known as dipeptidyl peptidase I (DPP-I) is a lysosomal exo-cysteine protease belonging to the peptidase C1 protein family, a subgroup of the cysteine cathepsins. In humans, it is encoded by the CTSC gene.

<span class="mw-page-title-main">Cathepsin G</span> Protein-coding gene in the species Homo sapiens

Cathepsin G is a protein that in humans is encoded by the CTSG gene. It is one of the three serine proteases of the chymotrypsin family that are stored in the azurophil granules, and also a member of the peptidase S1 protein family. Cathepsin G plays an important role in eliminating intracellular pathogens and breaking down tissues at inflammatory sites, as well as in anti-inflammatory response.

<span class="mw-page-title-main">Aspartic protease</span>

Aspartic proteases are a catalytic type of protease enzymes that use an activated water molecule bound to one or more aspartate residues for catalysis of their peptide substrates. In general, they have two highly conserved aspartates in the active site and are optimally active at acidic pH. Nearly all known aspartyl proteases are inhibited by pepstatin.

<span class="mw-page-title-main">Cathepsin B</span> Protein-coding gene in the species Homo sapiens

Cathepsin B belongs to a family of lysosomal cysteine proteases known as the cysteine cathepsins and plays an important role in intracellular proteolysis. In humans, cathepsin B is encoded by the CTSB gene. Cathepsin B is upregulated in certain cancers, in pre-malignant lesions, and in various other pathological conditions.

<span class="mw-page-title-main">Caspase 3</span> Protein-coding gene in the species Homo sapiens

Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the CASP3 gene. CASP3 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">GLB1</span> Protein

Galactosidase, beta 1, also known as GLB1, is a protein which in humans is encoded by the GLB1 gene.

<span class="mw-page-title-main">Cathepsin L1</span> Protein-coding gene in the species Homo sapiens

Cathepsin L1 is a protein that in humans is encoded by the CTSL1 gene. The protein is a cysteine cathepsin, a lysosomal cysteine protease that plays a major role in intracellular protein catabolism.

<span class="mw-page-title-main">SLPI</span> Protein-coding gene in the species Homo sapiens

Antileukoproteinase, also known as secretory leukocyte protease inhibitor (SLPI), is an enzyme that in humans is encoded by the SLPI gene. SLPI is a highly cationic single-chain protein with eight intramolecular disulfide bonds. It is found in large quantities in bronchial, cervical, and nasal mucosa, saliva, and seminal fluids. SLPI inhibits human leukocyte elastase, human cathepsin G, human trypsin, neutrophil elastase, and mast cell chymase. X-ray crystallography has shown that SLPI has two homologous domains of 53 and 54 amino acids, one of which exhibits anti-protease activity. The other domain is not known to have any function.

<span class="mw-page-title-main">LAMP1</span> Protein-coding gene in the species Homo sapiens

Lysosomal-associated membrane protein 1 (LAMP-1) also known as lysosome-associated membrane glycoprotein 1 and CD107a, is a protein that in humans is encoded by the LAMP1 gene. The human LAMP1 gene is located on the long arm (q) of chromosome 13 at region 3, band 4 (13q34).

<span class="mw-page-title-main">Cathepsin E</span> Protein-coding gene in the species Homo sapiens

Cathepsin E is an enzyme that in humans is encoded by the CTSE gene. The enzyme is also known as slow-moving proteinase, erythrocyte membrane aspartic proteinase, SMP, EMAP, non-pepsin proteinase, cathepsin D-like acid proteinase, cathepsin E-like acid proteinase, cathepsin D-type proteinase) is an enzyme.

<span class="mw-page-title-main">Cathepsin Z</span> Protein-coding gene in the species Homo sapiens

Cathepsin Z, also called cathepsin X or cathepsin P, is a protein that in humans is encoded by the CTSZ gene. It is a member of the cysteine cathepsin family of cysteine proteases, which has 11 members. As one of the 11 cathepsins, cathepsin Z contains distinctive features from others. Cathepsin Z has been reported involved in cancer malignancy and inflammation.

<span class="mw-page-title-main">LGMN</span> Protein-coding gene in the species Homo sapiens

Legumain is a protein that in humans is encoded by the LGMN gene.

<span class="mw-page-title-main">Cathepsin L2</span> Protein-coding gene in the species Homo sapiens

Cathepsin L2 is a protein encoded in humans by the CTSV gene.

<span class="mw-page-title-main">Cathepsin F</span> Protein-coding gene in the species Homo sapiens (Humans)

Cathepsin F is a protein that in humans is encoded by the CTSF gene.

<span class="mw-page-title-main">Papain-like protease</span>

Papain-like proteases are a large protein family of cysteine protease enzymes that share structural and enzymatic properties with the group's namesake member, papain. They are found in all domains of life. In animals, the group is often known as cysteine cathepsins or, in older literature, lysosomal peptidases. In the MEROPS protease enzyme classification system, papain-like proteases form Clan CA. Papain-like proteases share a common catalytic dyad active site featuring a cysteine amino acid residue that acts as a nucleophile.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000117984 - Ensembl, May 2017
  2. 1 2 3 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): 4910–4. Bibcode:1985PNAS...82.4910F. doi: 10.1073/pnas.82.15.4910 . PMC   390467 . PMID   3927292.
  6. 1 2 "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): 601–7. 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): 13403–6. doi: 10.1016/S0021-9258(18)80010-2 . PMID   2760027.
  9. 1 2 Saftig P, Hetman M, Schmahl W, Weber K, Heine L, Mossmann H, Köster A, Hess B, Evers M, von Figura K (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): 3599–608. doi:10.1002/j.1460-2075.1995.tb00029.x. PMC   394433 . PMID   7641679.
  10. 1 2 Ramirez-Montealegre D, Rothberg PG, Pearce DA (June 2006). "Another disorder finds its gene". Brain. 129 (Pt 6): 1353–6. 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): 1293–302. 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 / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society. 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): 3688–92. 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): 9437–46. 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): 866–71. 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): 5406–15. doi: 10.1074/jbc.M504670200 . PMID   16354654.
  18. 1 2 Hakala 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 . PMID   12750117.
  19. ↑ 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. PMID   9337526.
  20. 1 2 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): 5155–64. doi: 10.1242/jcs.01396 . PMID   15456852.
  22. ↑ Jha, Sawan Kumar; Rauniyar, Khushbu; Chronowska, Ewa; Mattonet, Kenny; Maina, Eunice Wairimu; Koistinen, Hannu; Stenman, Ulf-Håkan; Alitalo, Kari; Jeltsch, Michael (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. PMC   6588350 . PMID   31099754.
  23. ↑ 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 . 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): 1183–90. 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, 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. PMID   11304834.
  26. ↑ 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 . 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): 259–62. 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, 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 . PMID   21709160.
  30. ↑ 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. PMID   16784755. S2CID   34224448.
  31. ↑ 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 (October 1999). "Cathepsin D targeted by acid sphingomyelinase-derived ceramide". The EMBO Journal. 18 (19): 5252–63. doi:10.1093/emboj/18.19.5252. PMC   1171596 . PMID   10508159.

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