Cathepsin E is an enzyme (EC3.4.23.34) that in humans is encoded by the CTSEgene.[5][6][7] 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.[8][9][10][6]
Cathepsin E is a protease found in animals, as well as various other organisms, that belongs to the aspartic protease group. In humans it is encoded by the CTSE gene located at 1q32 on chromosome 1.[11][12][6][13] It is an intracellular non-lysosomal glycoprotein that is mainly found in the skin and in immune cells.[14] The protein is an aspartyl protease that functions as a disulfide-linked homodimer, and has an oligosaccharide chain of the high-mannose type.[15] It is a member of the peptidase A1 family, and therefore observes specificity similar to that of Pepsin A and Cathepsin D. Cathepsin E is an intracellular enzyme and does not appear to be involved in dietary protein digestion. It is found at highest abundance on the stomach’s epithelial mucus producing cell surfaces. It is the first aspartic protease present in the fetal stomach and is found in more than half of gastric cancers, leading to it appearing to be an oncofetal antigen. Transcript variants utilizing alternative polyadenylation signals and two transcript variants encoding different isoforms exist for this gene.[13][14]
A deficiency in the levels of Cathepsin E in the body may play a part in inflammatory skin diseases such as atopic dermatitis, for which treatment would rely on fixing functionality and levels of the protein in the body.[16] Along with renin and Cathepsin D, Cathepsin E is one of the only few aspartic proteases known to be made in human tissues other than those of gastrointestinal and reproductive tracts.[17]
Structure
The structure of Cathepsin E is very similar to those of Cathepsin D and BACE1, and all 3 have almost identical active site regions. The differences between them lie in the microenvironments that surround their active sites. Residues DTG 96-98 and DTG 281-283 contribute to the formation of the enzyme’s active site. There are also two pairs of disulfide bonds at residues Cys 272-276 and Cys 314-351. Two other Cys residues at positions 109 and 114 on the amino acid chain reside close to teach other in three dimensional space, however the distance between their sulfur atoms is 3.53 Å which is too large for the formation of a proper disulfide bond. The structure also has four hydrogen bonds between the Asp residues of the active site and the surrounding residues. A distinguishing factor of Cathepsin E in comparison with the structure of Cathepsin D and BACE1 can be seen at the formation of an extra hydrogen bond between the Asp 96 and Ser 99 residues, and absence of a hydrogen bond with Leu/Met at Asp 281.[16]
Location
The enzyme is distributed in cells of the gastrointestinal tracts, lymphoid tissues, blood cells, urinary organs and microglia. Its intracellular localization in different mammalian cells is different to that of its analog Cathepsin D. Cathepsin E associates with the membrane tissue in the intracellular canaliculi of gastric parietal cells, bile canaliculi of hepatic cells, cells of the rinal proximal tubule in the kidney, epithelial cells in the intestine, trachea and bronchi, osteoclasts and even in erythrocytes. Its localization in the endosome structures can be seen in many different cell types such as antigen-presenting B cell lymphoblasts, gastric cells and microglia. Its presence is also detected in the cisternae of the cell’s endoplasmic reticulum.[15][18]
Function
Cathepsin E plays a vital role in protein degradation, antigen processing via the MHC class II pathway[13] and bioactive protein generation. The enzyme is also thought to be involved in age induced neuronal death pathway execution as well as the excessive stimulation of glutamate receptors with excitotoxins and transient forebrain ischemia. In an experiment carried out on rats, Cathepsin E was barely detected in the brain tissues of young rats, however in older rats its level was greatly increased in the neostriatum and cerebral cortex. The enzyme was also expressed at high levels in the activated microglia of the hippocampal CA1 region and in degenerating neurons for a week after transient forebrain ischemia.[18] Cathepsin E has a possible role in the development of well differentiated adenocarcinoma from intestinal metaplasia.[15] The enzyme also plays a part in association with dendritic cells where it generates the CD4 repertoire in response to self and foreign proteins.[19]
Post-translational modification
The enzyme is glycosylated. Different cell types contribute to the differences in the nature of the carbohydrate chain. A high mannose-type oligosaccharide is observed in the proenzyme in fibroblasts, however the mature enzyme can be seen with a complex-type oligosaccharide. In the membranes of erythrocytes, the mature enzyme and the pro-enzyme both have a complex-type oligosaccharide. Auto catalytic cleavage produces two forms of the enzyme, with Form 1 beginning at residue Ile 54 and Form 2 at Thr 57.[20]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Couvreur JM, Azuma T, Miller DA, Rocchi M, Mohandas TK, Boudi FA, Taggart RT (Aug 1990). "Assignment of cathepsin E (CTSE) to human chromosome region 1q31 by in situ hybridization and analysis of somatic cell hybrids". Cytogenetics and Cell Genetics. 53 (2–3): 137–9. doi:10.1159/000132914. PMID2369841.
^Lapresle C, Puizdar V, Porchon-Bertolotto C, Joukoff E, Turk V (June 1986). "Structural differences between rabbit cathepsin E and cathepsin D". Biological Chemistry Hoppe-Seyler. 367 (6): 523–6. doi:10.1515/bchm3.1986.367.1.523. PMID3741628.
^Yonezawa S, Fujii K, Maejima Y, Tamoto K, Mori Y, Muto N (November 1988). "Further studies on rat cathepsin E: subcellular localization and existence of the active subunit form". Archives of Biochemistry and Biophysics. 267 (1): 176–83. doi:10.1016/0003-9861(88)90021-5. PMID3058036.
^Couvreur JM, Azuma T, Miller DA, Rocchi M, Mohandas TK, Boudi FA, Taggart RT (1990). "Assignment of cathepsin E (CTSE) to human chromosome region 1q31 by in situ hybridization and analysis of somatic cell hybrids". Cytogenetics and Cell Genetics. 53 (2–3): 137–9. doi:10.1159/000132914. PMID2369841.
^ abcZaidi N, Kalbacher H (March 2008). "Cathepsin E: a mini review". Biochemical and Biophysical Research Communications. 367 (3): 517–22. doi:10.1016/j.bbrc.2007.12.163. PMID18178150.
^ abYasuda Y, Kageyama T, Akamine A, Shibata M, Kominami E, Uchiyama Y, Yamamoto K (June 1999). "Characterization of new fluorogenic substrates for the rapid and sensitive assay of cathepsin E and cathepsin D". Journal of Biochemistry. 125 (6): 1137–43. doi:10.1093/oxfordjournals.jbchem.a022396. PMID10348917.
^ abcSaku T, Sakai H, Shibata Y, Kato Y, Yamamoto K (December 1991). "An immunocytochemical study on distinct intracellular localization of cathepsin E and cathepsin D in human gastric cells and various rat cells". Journal of Biochemistry. 110 (6): 956–64. doi:10.1093/oxfordjournals.jbchem.a123696. PMID1794985.
^ abChou KC (May 2005). "Modeling the tertiary structure of human cathepsin-E". Biochemical and Biophysical Research Communications. 331 (1): 56–60. doi:10.1016/j.bbrc.2005.03.123. PMID15845357.
^ abTsukuba T, Okamoto K, Yasuda Y, Morikawa W, Nakanishi H, Yamamoto K (December 2000). "New functional aspects of cathepsin D and cathepsin E". Molecules and Cells. 10 (6): 601–11. doi:10.1007/s10059-000-0601-8. PMID11211863. S2CID20761872.
Saku T, Sakai H, Shibata Y, Kato Y, Yamamoto K (December 1991). "An immunocytochemical study on distinct intracellular localization of cathepsin E and cathepsin D in human gastric cells and various rat cells". Journal of Biochemistry. 110 (6): 956–64. doi:10.1093/oxfordjournals.jbchem.a123696. PMID1794985.
Athauda SB, Takahashi T, Inoue H, Ichinose M, Takahashi K (November 1991). "Proteolytic activity and cleavage specificity of cathepsin E at the physiological pH as examined towards the B chain of oxidized insulin". FEBS Letters. 292 (1–2): 53–6. doi:10.1016/0014-5793(91)80832-N. PMID1959628. S2CID5501514.
Athauda SB, Matsuzaki O, Kageyama T, Takahashi K (April 1990). "Structural evidence for two isozymic forms and the carbohydrate attachment site of human gastric cathepsin E". Biochemical and Biophysical Research Communications. 168 (2): 878–85. doi:10.1016/0006-291X(90)92403-M. PMID2334440.
Takeda-Ezaki M, Yamamoto K (August 1993). "Isolation and biochemical characterization of procathepsin E from human erythrocyte membranes". Archives of Biochemistry and Biophysics. 304 (2): 352–8. doi:10.1006/abbi.1993.1361. PMID8346912.
Schulz TF, Reeves JD, Hoad JG, Tailor C, Stephens P, Clements G, Ortlepp S, Page KA, Moore JP, Weiss RA (February 1993). "Effect of mutations in the V3 loop of HIV-1 gp120 on infectivity and susceptibility to proteolytic cleavage". AIDS Research and Human Retroviruses. 9 (2): 159–66. doi:10.1089/aid.1993.9.159. PMID8457383.
Finzi G, Cornaggia M, Capella C, Fiocca R, Bosi F, Solcia E, Samloff IM (March 1993). "Cathepsin E in follicle associated epithelium of intestine and tonsils: localization to M cells and possible role in antigen processing". Histochemistry. 99 (3): 201–11. doi:10.1007/BF00269138. PMID8491674. S2CID6045937.
Sealy L, Mota F, Rayment N, Tatnell P, Kay J, Chain B (August 1996). "Regulation of cathepsin E expression during human B cell differentiation in vitro". European Journal of Immunology. 26 (8): 1838–43. doi:10.1002/eji.1830260826. PMID8765029. S2CID29006370.
Bernstein HG, Reichenbach A, Wiederanders B (January 1998). "Cathepsin E immunoreactivity in human ocular tissues: influence of aging and pathological states". Neuroscience Letters. 240 (3): 135–8. doi:10.1016/S0304-3940(97)00946-4. PMID9502222. S2CID9176410.
