Lympho-epithelial Kazal-type-related inhibitor (LEKTI) also known as serine protease inhibitor Kazal-type 5 (SPINK5) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''SPINK5''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Structure and function
LEKTI is a large multidomain
serine protease
Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site.
They are found ubiquitously in both eukaryotes and prokaryotes. Serin ...
inhibitor
Inhibitor or inhibition may refer to:
Biology
* Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity
* Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...
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 (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
s responsible for 3 intramolecular
disulfide bond
In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups.
In inor ...
s 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
The beta sheet (β-sheet, also β-pleated sheet) is a common structural motif, motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone chain, backbon ...
. All domains (excepting 1, 2 and 15) contain an
arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
at P1, indicating trypsin-like proteases are the likely targets.
In the epidermis, LEKTI is implicated in the regulation of
desquamation
Desquamation, or peeling skin, is the shedding of dead cells from the outermost layer of skin.
The term is .
Physiologic desquamation
Keratinocytes are the predominant cells of the epidermis, the outermost layer of the skin. Living keratin ...
via its ability to selectively inhibit
KLK5,
KLK7
Kallikrein-related peptidase 7 (KLK7) 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 (SCCE). It was later identified as ...
and
KLK14.
full length LEKTI inhibits the exogenous serine proteases
trypsin
Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the dig ...
,
plasmin
Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin thrombus, clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) i ...
,
subtilisin A,
cathepsin G and human neutrophil
elastase.
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 5q32,
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.
[
] 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 result in
Netherton syndrome, a disorder characterized by
ichthyosis
Ichthyosis is a family of genetic disorder, genetic skin disorders characterized by Xeroderma, dry, Scleroderma, thickened, scaly skin. The more than 20 types of ichthyosis range in severity of symptoms, outward appearance, underlying genetic cau ...
and specific immune system defects.
See also
*
Kazal-type serine protease inhibitor domain
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
External links
*
{{gene-5-stub