Biology:KLK7

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Kallikrein-related peptidase 7 (KLK7) is a serine protease that in humans is encoded by the KLK7 gene.[1][2][3][4] KLK7 was initially purified from the epidermis and characterised as stratum corneum chymotryptic enzyme (SCCE).[5] It was later identified as the seventh member of the human kallikrein family, which includes fifteen homologous serine proteases located on chromosome 19 (19q13).[6]

Gene

Alternative splicing of the KLK7 gene results in two transcript variants encoding the same protein.[4]

Function

KLK7 is secreted as an inactive zymogen in the stratum granulosum layer of the epidermis, requiring proteolytic cleavage of the short N-terminal pro-region to liberate activated enzyme. This may be performed by KLK5 or matriptase, which are in vitro activators of KLK7.[7][8]

Once active, KLK7 is able to cleave desmocollin and corneodesmosin.[9] These proteins constitute the extracellular component of corneodesmosomes, intercellular cohesive structures which link the intermediate filaments of adjacent cells in the stratum corneum. Proteolysis of corneodesmosomes is required for desquamation, the shedding of corneocytes from the outer layer of the epidermis. This indicates a role for KLK7 in maintaining skin homeostasis. For example, KLK7 expression is highly downregulated at acral surfaces where desquamation is delayed and the epidermis is thick.[10]

Both KLK5 and KLK14, other skin-expressed proteases, also cleave corneodesmosomal proteins.[9] KLK5 is able to undergo autoactivation, as well as activating KLK7 and KLK14, suggesting a KLK skin cascade is responsible for coordinating desquamation.[8]

KLK7 activity is regulated by a number of endogenous protein inhibitors including LEKTI,[11][12] SPINK6,[13] elafin[14] and alpha-2-Macroglobulin-like 1.[15] Both Zn2+ and Cu2+ ions are also able to inhibit KLK7.[14]

KLK7 is a chymotrypsin-like serine protease, preferring to cleave proteins at the residues tyrosine, phenylalanine or leucine.[16] Analysis of peptide substrate hydrolysis indicates a strong preference for tyrosine at P1.[17]

Clinical significance

Skin disease

Dysregulation of KLK7 has been linked to several skin disorders including atopic dermatitis,[18][19] psoriasis[20] and Netherton syndrome.[21][22] These diseases are characterised by excessively dry, scaly and inflamed skin, due to a disruption of skin homeostasis and correct barrier function.

Cancer

Overexpression of KLK7 may provide a route for metastasis in ovarian,[23] breast,[24] pancreatic,[25] cervix,[26] and melanoma[27] cancers by excessive cleavage of cell junction proteins. It may also be underexpressed in lung cancer.[28]

References

  1. ↑ "Cloning, expression, and characterization of stratum corneum chymotryptic enzyme. A skin-specific human serine proteinase". The Journal of Biological Chemistry 269 (30): 19420–19426. July 1994. doi:10.1016/S0021-9258(17)32185-3. PMID 8034709. 
  2. ↑ "A comprehensive nomenclature for serine proteases with homology to tissue kallikreins". Biological Chemistry 387 (6): 637–641. June 2006. doi:10.1515/BC.2006.082. PMID 16800724. https://epub.ub.uni-muenchen.de/17786/1/bc.2006.082.pdf. 
  3. ↑ "Proceedings of the 1st International Symposium on Kallikreins, Lausanne, Switzerland, September 1-3 , 2005". Biological Chemistry 387 (6): 635–824. June 2006. doi:10.1515/BC.2006.081. PMID 16800723. 
  4. ↑ 4.0 4.1 "Entrez Gene: KLK7 kallikrein-related peptidase 7". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5650. 
  5. ↑ "Stratum corneum chymotryptic enzyme: a proteinase which may be generally present in the stratum corneum and with a possible involvement in desquamation". Acta Dermato-Venereologica 71 (6): 471–474. 1991. doi:10.2340/0001555571471474. PMID 1685827. 
  6. ↑ "The KLK7 (PRSS6) gene, encoding for the stratum corneum chymotryptic enzyme is a new member of the human kallikrein gene family - genomic characterization, mapping, tissue expression and hormonal regulation". Gene 254 (1–2): 119–128. August 2000. doi:10.1016/S0378-1119(00)00280-8. PMID 10974542. 
  7. ↑ "Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome". Nature Genetics 42 (8): 676–683. August 2010. doi:10.1038/ng.629. PMID 20657595. 
  8. ↑ 8.0 8.1 "A proteolytic cascade of kallikreins in the stratum corneum". The Journal of Investigative Dermatology 124 (1): 198–203. January 2005. doi:10.1111/j.0022-202X.2004.23547.x. PMID 15654974. 
  9. ↑ 9.0 9.1 "Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7". The Journal of Investigative Dermatology 122 (5): 1235–1244. May 2004. doi:10.1111/j.0022-202X.2004.22512.x. PMID 15140227. 
  10. ↑ "Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes". JCI Insight 7 (16): e159762. August 2022. doi:10.1172/jci.insight.159762. PMID 35900871. 
  11. ↑ "LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction". Molecular Biology of the Cell 18 (9): 3607–3619. September 2007. doi:10.1091/mbc.e07-02-0124. PMID 17596512. 
  12. ↑ "hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6". The British Journal of Dermatology 153 (6): 1200–1203. December 2005. doi:10.1111/j.1365-2133.2005.06834.x. PMID 16307658. 
  13. ↑ "Isolation of SPINK6 in human skin: selective inhibitor of kallikrein-related peptidases". The Journal of Biological Chemistry 285 (42): 32174–32181. October 2010. doi:10.1074/jbc.M109.091850. PMID 20667819. 
  14. ↑ 14.0 14.1 "Antileukoprotease inhibits stratum corneum chymotryptic enzyme. Evidence for a regulative function in desquamation". The Journal of Biological Chemistry 271 (36): 21886–21890. September 1996. doi:10.1074/jbc.271.36.21886. PMID 8702990. 
  15. ↑ "A novel protease inhibitor of the alpha2-macroglobulin family expressed in the human epidermis". The Journal of Biological Chemistry 281 (9): 5780–5789. March 2006. doi:10.1074/jbc.m508017200. PMID 16298998. 
  16. ↑ "Primary substrate specificity of recombinant human stratum corneum chymotryptic enzyme". Biochemical and Biophysical Research Communications 211 (2): 586–589. June 1995. doi:10.1006/bbrc.1995.1853. PMID 7794273. 
  17. ↑ "Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences". The Journal of Biological Chemistry 281 (35): 25678–25688. September 2006. doi:10.1074/jbc.M602372200. PMID 16740631. 
  18. ↑ "Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients". Experimental Dermatology 16 (6): 513–519. June 2007. doi:10.1111/j.1600-0625.2007.00562.x. PMID 17518992. 
  19. ↑ "Genetic association between an AACC insertion in the 3'UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis". The Journal of Investigative Dermatology 123 (1): 62–66. July 2004. doi:10.1111/j.0022-202X.2004.22708.x. PMID 15191543. 
  20. ↑ "Stratum corneum chymotryptic enzyme in psoriasis". Archives of Dermatological Research 291 (4): 195–200. April 1999. doi:10.1007/s004030050393. PMID 10335915. 
  21. ↑ "Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity". Nature Genetics 37 (1): 56–65. January 2005. doi:10.1038/ng1493. PMID 15619623. 
  22. ↑ "Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome". The Journal of Investigative Dermatology 126 (7): 1622–1632. July 2006. doi:10.1038/sj.jid.5700284. PMID 16628198. 
  23. ↑ "Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers". Clinical Cancer Research 9 (5): 1710–1720. May 2003. PMID 12738725. 
  24. ↑ "Expression analysis of the human kallikrein 7 (KLK7) in breast tumors: a new potential biomarker for prognosis of breast carcinoma". Thrombosis and Haemostasis 91 (1): 180–186. January 2004. doi:10.1160/TH03-05-0261. PMID 14691584. 
  25. ↑ "Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E-cadherin". Cancer 109 (9): 1811–1820. May 2007. doi:10.1002/cncr.22606. PMID 17354228. 
  26. ↑ "The serine protease stratum corneum chymotryptic enzyme (kallikrein 7) is highly overexpressed in squamous cervical cancer cells". Gynecologic Oncology 94 (2): 283–288. August 2004. doi:10.1016/j.ygyno.2004.05.023. PMID 15297163. 
  27. ↑ "Cell adhesion and communication proteins are differentially expressed in melanoma progression model". Human Pathology 42 (3): 409–418. March 2011. doi:10.1016/j.humpath.2010.09.004. PMID 21193224. 
  28. ↑ "KLK5 and KLK7, two members of the human tissue kallikrein family, are differentially expressed in lung cancer". Biochemical and Biophysical Research Communications 329 (4): 1260–1266. April 2005. doi:10.1016/j.bbrc.2005.02.100. PMID 15766562. 

Further reading

External links

  • The MEROPS online database for peptidases and their inhibitors: S01.017



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