LEKTI explained

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 SPINK5 gene.^{[1] [2]}

Structure and function

LEKTI is a large multidomain serine protease inhibitor 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. 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.

In the epidermis, LEKTI is implicated in the regulation of desquamation via its ability to selectively inhibit KLK5, KLK7 and KLK14.^[3] Recombinant full length LEKTI inhibits the exogenous serine proteases trypsin, plasmin, subtilisin A, cathepsin G and human neutrophil elastase.^[4]

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,^[5] 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.^[6] Alternative processing of SPINK5 results in the formation of three different gene products, which have been identified in differentiated keratinocytes.^[7]

Clinical significance

Mutations in the SPINK5 gene result in Netherton syndrome, a disorder characterized by ichthyosis and specific immune system defects.^[2]

See also

• Kazal-type serine protease inhibitor domain

Further reading

• Norgett EE, Kelsell DP . SPINK5: both rare and common skin disease. . Trends in Molecular Medicine . 8 . 1 . 7 . 2002 . 11796258 . 10.1016/S1471-4914(01)02228-6 .
• Mägert HJ, Kreutzmann P, Ständker L, etal . LEKTI: a multidomain serine proteinase inhibitor with pathophysiological relevance. . Int. J. Biochem. Cell Biol. . 34 . 6 . 573–6 . 2002 . 11943586 . 10.1016/S1357-2725(01)00179-0 .
• Walden M, Kreutzmann P, Drögemüller K, etal . Biochemical features, molecular biology and clinical relevance of the human 15-domain serine proteinase inhibitor LEKTI. . Biol. Chem. . 383 . 7–8 . 1139–41 . 2003 . 12437098 . 10.1515/BC.2002.124 . 26084613 .
• Chavanas S, Garner C, Bodemer C, etal . Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping. . Am. J. Hum. Genet. . 66 . 3 . 914–21 . 2000 . 10712206 . 10.1086/302824 . 1288172 .
• Chavanas S, Bodemer C, Rochat A, etal . Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. . Nat. Genet. . 25 . 2 . 141–2 . 2000 . 10835624 . 10.1038/75977 . 40421711 .
• Sprecher E, Chavanas S, DiGiovanna JJ, etal . 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 . 2001 . 11511292 . 10.1046/j.1523-1747.2001.01389.x . free .
• Walley AJ, Chavanas S, Moffatt MF, etal . Gene polymorphism in Netherton and common atopic disease. . Nat. Genet. . 29 . 2 . 175–8 . 2001 . 11544479 . 10.1038/ng728 . 20292050 .
• Ahmed A, Kandola P, Ziada G, Parenteau N . Purification and partial amino acid sequence of proteins from human epidermal keratinocyte conditioned medium. . J. Protein Chem. . 20 . 4 . 273–8 . 2002 . 11594460 . 10.1023/A:1010902815953 . 11877191 .
• Bitoun E, Chavanas S, Irvine AD, etal . Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. . J. Invest. Dermatol. . 118 . 2 . 352–61 . 2002 . 11841556 . 10.1046/j.1523-1747.2002.01603.x . free .
• Komatsu N, Takata M, Otsuki N, etal . 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 . 2002 . 11874482 . 10.1046/j.0022-202x.2001.01663.x . free . 2297/15796 . free .
• Bitoun E, Micheloni A, Lamant L, etal . LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. . Hum. Mol. Genet. . 12 . 19 . 2417–30 . 2004 . 12915442 . 10.1093/hmg/ddg247 . free .
• Nishio Y, Noguchi E, Shibasaki M, etal . Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese. . Genes Immun. . 4 . 7 . 515–7 . 2004 . 14551605 . 10.1038/sj.gene.6363889 . free .
• Raghunath M, Tontsidou L, Oji V, etal . SPINK5 and Netherton syndrome: novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases. . J. Invest. Dermatol. . 123 . 3 . 474–83 . 2004 . 15304086 . 10.1111/j.0022-202X.2004.23220.x . free .
• Tidow H, Lauber T, Vitzithum K, etal . The solution structure of a chimeric LEKTI domain reveals a chameleon sequence. . Biochemistry . 43 . 35 . 11238–47 . 2004 . 15366933 . 10.1021/bi0492399 .
• Yang T, Liang D, Koch PJ, etal . Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice. . Genes Dev. . 18 . 19 . 2354–8 . 2004 . 15466487 . 10.1101/gad.1232104 . 522985 .
• Ishida-Yamamoto A, Deraison C, Bonnart C, etal . 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 . 2005 . 15675955 . 10.1111/j.0022-202X.2004.23583.x . free .

Notes and References

1. Magert HJ, Standker L, Kreutzmann P, Zucht HD, Reinecke M, Sommerhoff CP, Fritz H, Forssmann WG . LEKTI, a novel 15-domain type of human serine proteinase inhibitor . J Biol Chem . 274 . 31 . 21499–502 . Aug 1999 . 10419450 . 10.1074/jbc.274.31.21499 . free .
2. Web site: Entrez Gene: SPINK5 serine peptidase inhibitor, Kazal type 5.
3. Deraison C, Bonnart C, Lopez F, Besson C, Robinson R, Jayakumar A, Wagberg F, Brattsand M, Hachem JP, Leonardsson G, Hovnanian A . LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction . Mol. Biol. Cell . 18 . 9 . 3607–19 . September 2007 . 17596512 . 1951746 . 10.1091/mbc.E07-02-0124 .
4. Mitsudo K, Jayakumar A, Henderson Y, Frederick MJ, Kang Y, Wang M, El-Naggar AK, Clayman GL . Inhibition of serine proteinases plasmin, trypsin, subtilisin A, cathepsin G, and elastase by LEKTI: a kinetic analysis. . Biochemistry . 42 . 13 . 3874–81 . April 2003 . 12667078 . 10.1021/bi027029v.
5. Web site: SPINK5 serine peptidase inhibitor, Kazal type 5 [Homo sapiens (human)] - Gene - NCBI.
6. Furio L, Hovnanian A . When Activity Requires Breaking Up: LEKTI Proteolytic Activation Cascade for Specific Proteinase Inhibition. . J Invest Dermatol . 131 . 11 . 2169–73 . November 2011 . 21997416 . 10.1038/jid.2011.295 . free .
7. Tartaglia-Polcini A, Bonnart C, Micheloni A, Cianfarani F, Andrè A, Zambruno G, Hovnanian A, D'Alessio M . SPINK5, the defective gene in netherton syndrome, encodes multiple LEKTI isoforms derived from alternative pre-mRNA processing. . J Invest Dermatol . 126 . 2 . 315–24 . February 2006 . 16374478 . 10.1038/sj.jid.5700015. free .