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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''SPINK5''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
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. Seri ...
inhibitor
Inhibitor or inhibition may refer to:
In 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 neurotra ...
expressed in stratified epithelial tissue. It consists of 15 domains that are cleaved into smaller, functional fragments by the protease
furin
Furin is a protease, a proteolytic enzyme that in humans and other animals is encoded by the ''FURIN'' gene. Some proteins are inactive when they are first synthesized, and must have sections removed in order to become active. Furin cleaves these s ...
. 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 formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, some ...
s responsible for 3 intramolecular
disulfide bond
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
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 motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a ge ...
. 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 guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
at P1, indicating trypsin-like proteases are the likely targets.
In the epidermis, LEKTI is implicated in the regulation of
desquamation
Desquamation occurs when the outermost layer of a tissue, such as the skin, is shed. The term is . Physiologic desquamation
Keratinocytes are the predominant cells of the epidermis, the outermost layer of the skin. Living keratinocytes reside in ...
via its ability to selectively inhibit
KLK5
Kallikrein-5, formerly known as stratum corneum tryptic enzyme (SCTE), 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 cl ...
,
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 t ...
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 these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the d ...
,
plasmin
Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encode ...
,
subtilisin A,
cathepsin G and human neutrophil
elastase
In molecular biology, elastase is an enzyme from the class of ''proteases (peptidases)'' that break down proteins. In particular, it is a serine protease.
Forms and classification
Eight human genes exist for elastase:
Some bacteria (includin ...
.
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 skin disorders characterized by dry, thickened, scaly skin. The more than 20 types of ichthyosis range in severity of symptoms, outward appearance, underlying genetic cause and mode of inheritance (e.g., dominant ...
and specific immune system defects.
See also
*
Kazal-type serine protease inhibitor domain
References
Further reading
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External links
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{{gene-5-stub