LEKTI

LEKTI is the acronym for "lympho-epithelial Kazal-type-related inhibitor", also known as "serine protease inhibitor Kazal-type 5" or SPINK5. LEKTI is a serine protease inhibitor. In humans, the inhibitory protein is encoded by the SPINK5 gene. Mutations of the SPINK5 gene are associated with Netherton syndrome.

LEKTI is a large multidomain serine protease inhibitor expressed in squamous epithelia. LEKTI 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 distributed cysteines, which are responsible for the 3 intramolecular disulfide bonds characteristic of related Kazal-type inhibitors. The remaining domains contain 4 cysteines. These disulfide bonds force the molecule into a rigid conformation that allows the protein to interact with a target protease. All domains (except 1, 2 and 15) contain an arginine at P1, suggesting that trypsin-like proteases are the likely targets.

In the epidermis, LEKTI is involved in the regulation of desquamation via its ability to selectively inhibit the serine proteases of the kallikrein-related peptidase (KLK) family 5, 7, 14. Recombinant full-length LEKTI inhibits the exogenous serine proteases trypsin, plasmin, subtilisin A, cathepsin G and human neutrophil elastase.

Furthermore, LEKTI domains 6, 7 and the functional unit of domains 8 and 9 contain recognition motifs for transglutaminase (TG)1. It is known that these domains are cross-linked into the epidermis by transglutaminase (TG)1. Functional analyses of the recombinant LEKTI domains showed thatLEKTI D8+9 exerts a strong inhibitory effect on kallikrein5 (KLK5) (Wiegmann H et al. 2019).

LEKTI may also play a role in skin and hair morphogenesis and in the anti-inflammatory and/or antimicrobial protection of mucosal epithelia.

The coding SPINK5 gene is 61 kb long and contains 33 exons. It is a member of a gene family cluster on chromosome 5q32 that codes for inhibitors of serine proteases. This also includes other epidermal proteins such as SPINK6 and LEKTI-2 (SPINK9).

Mutations in the SPINK5 gene lead to Netherton syndrome, a disorder characterized by ichthyosis and specific immune system defects.

1. Magert HJ et al. (1999) LEKTI, a novel 15-domain type of human serine proteinase inhibitor. J Biol Chem. 274: 21499-21502.
2. Furio L et al (2011) When Activity Requires Breaking Up: LEKTI proteolytic activation cascade for specific proteinase inhibition. J Invest Dermatol 131: 2169-2173.
3. Deraison C et al (2007). LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell 18: 3607-3619.
4. Mitsudo K et al. (2003) Inhibition of serine proteinases plasmin, trypsin, subtilisin A, cathepsin G, and elastase by LEKTI: a kinetic analysis. Biochemistry 42: 3874-3881.
5. Wiegmann H et al. (2019) LEKTI domains D6, D7 and D8+9 serve as substrates for transglutaminase 1: implications for targeted therapy of Netherton syndrome. Br J Dermatol 181:999-1008.