Kallikrein-related peptidase 7 (KLK7) is a

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. ...

that in humans is encoded by the ''KLK7''

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 ba ...

. KLK7 was initially purified from the

epidermis The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rele ...

and characterised as stratum corneum chymotryptic enzyme (SCCE). It was later identified as the seventh member of the human

kallikrein Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (encoded by '' KLKB1 gene'') has no known paralogue, while tissue kallikrein-related peptidases (''KLKs'') encode a ...

family, which includes fifteen homologous serine proteases located on

chromosome 19 Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 58.6 million base pairs, the building material of DNA. It is considered the most gene-rich chromosom ...

(19q13).

Gene

Alternative splicing of the ''KLK7'' gene results in two transcript variants encoding the same protein.

Function

KLK7 is secreted as an inactive

zymogen In biochemistry, a zymogen (), also called a proenzyme (), is an inactive precursor of an enzyme. A zymogen requires a biochemical change (such as a hydrolysis reaction revealing the active site, or changing the configuration to reveal the activ ...

in the

stratum granulosum The stratum granulosum (or granular layer) is a thin layer of cells in the epidermis lying above the stratum spinosum and below the stratum corneum (stratum lucidum on the soles and palms).James, William; Berger, Timothy; Elston, Dirk (2005) ''A ...

layer of the

, requiring proteolytic cleavage of the short N-terminal pro-region to liberate activated enzyme. This may be performed by

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 clust ...

or matriptase, which are ''in vitro'' activators of KLK7. Once active, KLK7 is able to cleave

desmocollin Desmocollins are a subfamily of desmosomal cadherins, the transmembrane constituents of desmosomes. They are co-expressed with desmogleins to link adjacent cells by extracellular adhesion. There are seven desmosomal cadherins in humans, three des ...

and

corneodesmosin Corneodesmosin is a protein that in humans is encoded by the ''CDSN'' gene. This gene encodes a protein found in corneodesmosomes, which localize to the human epidermis and other cornified squamous epithelia. During maturation of the cornified lay ...

. These proteins constitute the extracellular component of corneodesmosomes, intercellular cohesive structures which link the

intermediate filaments Intermediate filaments (IFs) are cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate '' Branchiostoma''. Intermedi ...

of adjacent cells in the stratum corneum. Proteolysis of corneodesmosomes is required for

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 ...

, the shedding of corneocytes from the outer layer of the epidermis. This indicates a role for KLK7 in maintaining skin

homeostasis In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...

. For example, KLK7 expression is highly downregulated at acral surfaces where desquamation is delayed and the epidermis is thick. Both KLK5 and

KLK14 Kallikrein-14 is a protein that in humans is encoded by the ''KLK14'' gene. Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis an ...

, other skin-expressed proteases, also cleave corneodesmosomal proteins. KLK5 is able to undergo autoactivation, as well as activating KLK7 and KLK14, suggesting a KLK skin cascade is responsible for coordinating desquamation. KLK7 activity is regulated by a number of endogenous protein inhibitors including

LEKTI 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. Structure and function LEKTI is a large multidomain serine prot ...

SPINK6 Serine protease inhibitor Kazal-type 6 (SPINK6) 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 membe ...

elafin Elafin, also known as peptidase inhibitor 3 or skin-derived antileukoprotease (SKALP), is a protein that in humans is encoded by the ''PI3'' gene. Function This gene encodes an elastase-specific protease inhibitor, which contains a WAP-type f ...

and

alpha-2-Macroglobulin-like 1 Alpha-2-macroglobulin-like 1 abbreviated as α2ML1 is a protein that in humans is encoded by the A2ML1 gene. α2ML1 is a large, 180 kDa protein found in the epidermis. It is able to the inhibit the chymotryptic activity of KLK7. Function This ...

. Both Zn²⁺ and Cu²⁺ ions are also able to inhibit KLK7. KLK7 is a chymotrypsin-like serine protease, preferring to cleave proteins at the residues

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...

leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- ca ...

. Analysis of peptide substrate hydrolysis indicates a strong preference for tyrosine at P1.

Clinical significance

Skin disease

Dysregulation of KLK7 has been linked to several skin disorders including atopic dermatitis,

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

and

Netherton syndrome Netherton syndrome is a severe, autosomal recessive form of ichthyosis associated with mutations in the ''SPINK5'' gene. It is named after Earl W. Netherton (1910–1985), an American dermatologist who discovered it in 1958.Netherton, E. W. A u ...

. These diseases are characterised by excessively dry, scaly and inflamed skin, due to a disruption of skin homeostasis and correct barrier function.

Cancer

Overexpression of KLK7 may provide a route for

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

ovarian The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body ...

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...

pancreatic The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an endocr ...

, cervix, and

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

cancers Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...

by excessive cleavage of cell junction proteins. It may also be underexpressed in

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissue (biology), tissues of the lung. Lung carcinomas derive from tran ...

References

External links

* The

MEROPS MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibitor ...

online database for peptidases and their inhibitors
S01.017
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