Lympho-epithelial Kazal-type-related inhibitor (LEKTI) also known as serine protease inhibitor Kazal-type 5 (SPINK5) is a protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that in humans is encoded by the SPINK5 gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

.

Structure and function

LEKTI is a large multidomain serine protease

Serine protease

Serine proteases are enzymes that cleave peptide bonds in proteins, in which serine serves as the nucleophilic amino acid at the active site.They are found ubiquitously in both eukaryotes and prokaryotes...

 inhibitor

Enzyme inhibitor

An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

 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 cysteine

Cysteine

Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

s responsible for 3 intramolecular disulphide bonds characteristic of Kazal-type related inhibitors

Kazal-type serine protease inhibitor domain

Kazal-type serine protease inhibitor domain is an evolutionary conserved protein domain.Usually indicative of serine protease inhibitors. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors.- Kazal_1 :Kazal domains often...

. The remaining domains contain 4 cysteines. These disulphide 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

Arginine

Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...

 at P1, indicating trypsin-like proteases are the likely targets.

In the epidermis, LEKTI is implicated in the regulation of desquamation

Desquamation

Desquamation , also called skin peeling, is the shedding of the outermost membrane or layer of a tissue, such as the skin.-Skin:Normal, nonpathologic desquamation of the skin occurs when keratinocytes, after moving apically over about 14 days, are individually shed unnoticeably...

 via its ability to selectively inhibit KLK5

KLK5

Kallikrein-related peptidase 5 , formerly known as stratum corneum tryptic enzyme , is a serine protease expressed in the epidermis. In humans it is encoded by the KLK5 gene. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. Its expression is...

, KLK7

KLK7

Kallikrein-related peptidase 7 is a serine protease that in humans is encoded by the KLK7 gene. KLK7 was initially purified from the epidermis and characterised as stratum corneum chymotryptic enzyme...

 and KLK14

KLK14

Kallikrein-14 is a protein that in humans is encoded by the KLK14 gene.-External Links:* The MEROPS online database for peptidases and their inhibitors:...

. Recombinant full length LEKTI inhibits the exogenous serine proteases trypsin

Trypsin

Trypsin is a serine protease found in the digestive system of many vertebrates, where it hydrolyses proteins. Trypsin is produced in the pancreas as the inactive proenzyme trypsinogen. Trypsin cleaves peptide chains mainly at the carboxyl side of the amino acids lysine or arginine, except when...

, plasmin

Plasmin

Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, most notably, fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.- Function :...

, subtilisin A

Subtilisin

Subtilisin is a non-specific protease initially obtained from Bacillus subtilis.Subtilisins belong to subtilases, a group of serine proteases that initiate the nucleophilic attack on the peptide bond through a serine residue at the active site. They are physically and chemically...

, cathepsin G

Cathepsin G

Cathepsin G is an enzymatic protein belonging to the peptidase or protease families. In humans, it is coded by the CTSG gene.The protein encoded by this gene, a member of the peptidase S1 protein family, is found in azurophil granules of neutrophilic polymorphonuclear leukocytes...

 and human neutrophil elastase

Elastase

In molecular biology, elastase is an enzyme from the class of proteases that break down proteins.- Forms and classification:There exist eight human genes for elastase:Bacterial forms: Organisms such as P...

.

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

Gene

SPINK5 is a member of a gene family cluster located on chromosome

Chromosome

A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...

 5q33.1, which encode inhibitors of serine proteases. This includes other epidermal proteins SPINK6

SPINK6

Serine protease inhibitor Kazal-type 6 is a protein encoded by the SPINK6 gene in humans. It is a potent inhibitor of epidermal proteases involved in maintaining skin homeostasis, including KLK5, KLK7 and KLK14. SPINK6 is a member of a gene family cluster located on chromosome 5q33.1, which...

 and LEKTI-2

LEKTI-2

Lympho-epithelial Kazal-type related inhibitor 2 is a protein encoded by the SPINK9 gene in humans. LEKTI-2 is an inhibitor of KLK5, a serine protease expressed in the epidermis and responsible for coordinating skin homeostasis and desquamation. SPINK9 is a member of a gene family cluster located...

 (SPINK9). The SPINK5 gene is 61 kb in length and contains 33 exons. Alternative processing of SPINK5 results in the formation of three different gene products, which have been identified in differentiated keratinocytes.

Clinical significance

Mutations in the SPINK5 gene may result in Netherton syndrome

Netherton syndrome

Netherton syndrome is a severe, autosomal recessive form of ichthyosis associated with mutations in the SPINK5 gene. It is named after E.W. Netherton.- Characteristics :...

, a disorder characterized by ichthyosis

Ichthyosis

Ichthyosis is a heterogeneous family of at least 28, generalized, mostly genetic skin disorders. All types of ichthyosis have dry, thickened, scaly or flaky skin...

, defective cornification, and atopy

Atopy

Atopy or atopic syndrome is a predisposition toward developing certain allergic hypersensitivity reactions.Atopy may have a hereditary component, although contact with the allergen must occur before the hypersensitivity reaction can develop ....

.