Lympho-epithelial Kazal-type-related inhibitor (LEKTI) also known as serine protease inhibitor Kazal-type 5 (SPINK5) is a protein that in humans is encoded by the SPINK5gene.[1][2]
LEKTI is a large multidomain serine proteaseinhibitor expressed in stratified epithelial tissue. It consists of 15 domains that are cleaved into smaller, functional fragments by the protease furin. Only two of these domains (2 and 15) contain 6 evenly spaced cysteines responsible for 3 intramolecular disulfide bonds characteristic of Kazal-type related inhibitors. The remaining domains contain 4 cysteines.[3] These disulfide bonds force the molecule into a rigid conformation that enables the protein to interact with a target protease via an extended beta-sheet. All domains (excepting 1, 2 and 15) contain an arginine at P1, indicating trypsin-like proteases are the likely targets.[3]
LEKTI may play a role in skin and hair morphogenesis and anti-inflammatory and/or antimicrobial protection of mucous epithelia.[2]
Gene
SPINK5 is a member of a gene family cluster located on chromosome 5q32,[6] which encode inhibitors of serine proteases. This includes other epidermal proteins SPINK6 and LEKTI-2 (SPINK9). The SPINK5 gene is 61 kb in length and contains 33 exons.[3] Alternative processing of SPINK5 results in the formation of three different gene products, which have been identified in differentiated keratinocytes.[7]
↑Mitsudo K, Jayakumar A, Henderson Y, Frederick MJ, Kang Y, Wang M, El-Naggar AK, Clayman GL (April 2003). "Inhibition of serine proteinases plasmin, trypsin, subtilisin A, cathepsin G, and elastase by LEKTI: a kinetic analysis". Biochemistry. 42 (13): 3874–81. doi:10.1021/bi027029v. PMID12667078.
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Tartaglia-Polcini A, Bonnart C, Micheloni A, Cianfarani F, Andrè A, Zambruno G, Hovnanian A, D'Alessio M (February 2006). "SPINK5, the defective gene in netherton syndrome, encodes multiple LEKTI isoforms derived from alternative pre-mRNA processing". J Invest Dermatol. 126 (2): 315–24. doi:10.1038/sj.jid.5700015. PMID16374478.
Chavanas S, Bodemer C, Rochat A, et al. (2000). "Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome". Nat. Genet. 25 (2): 141–2. doi:10.1038/75977. PMID10835624.
Sprecher E, Chavanas S, DiGiovanna JJ, et al. (2001). "The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis". J. Invest. Dermatol. 117 (2): 179–87. doi:10.1046/j.1523-1747.2001.01389.x. PMID11511292.
Walley AJ, Chavanas S, Moffatt MF, et al. (2001). "Gene polymorphism in Netherton and common atopic disease". Nat. Genet. 29 (2): 175–8. doi:10.1038/ng728. PMID11544479.
Ahmed A, Kandola P, Ziada G, Parenteau N (2002). "Purification and partial amino acid sequence of proteins from human epidermal keratinocyte conditioned medium". J. Protein Chem. 20 (4): 273–8. doi:10.1023/A:1010902815953. PMID11594460.
Bitoun E, Chavanas S, Irvine AD, et al. (2002). "Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families". J. Invest. Dermatol. 118 (2): 352–61. doi:10.1046/j.1523-1747.2002.01603.x. PMID11841556.
Komatsu N, Takata M, Otsuki N, et al. (2002). "Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides". J. Invest. Dermatol. 118 (3): 436–43. doi:10.1046/j.0022-202x.2001.01663.x. PMID11874482.
Bitoun E, Micheloni A, Lamant L, et al. (2004). "LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome". Hum. Mol. Genet. 12 (19): 2417–30. doi:10.1093/hmg/ddg247. PMID12915442.
Nishio Y, Noguchi E, Shibasaki M, et al. (2004). "Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese". Genes Immun. 4 (7): 515–7. doi:10.1038/sj.gene.6363889. PMID14551605.
Raghunath M, Tontsidou L, Oji V, et al. (2004). "SPINK5 and Netherton syndrome: novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases". J. Invest. Dermatol. 123 (3): 474–83. doi:10.1111/j.0022-202X.2004.23220.x. PMID15304086.
Tidow H, Lauber T, Vitzithum K, et al. (2004). "The solution structure of a chimeric LEKTI domain reveals a chameleon sequence". Biochemistry. 43 (35): 11238–47. doi:10.1021/bi0492399. PMID15366933.
Ishida-Yamamoto A, Deraison C, Bonnart C, et al. (2005). "LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum". J. Invest. Dermatol. 124 (2): 360–6. doi:10.1111/j.0022-202X.2004.23583.x. PMID15675955.
