The Kazal domain is an evolutionary conserved

protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...

usually indicative of

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 ...

s. However, kazal-like domains are also seen in the extracellular part of

agrin Agrin is a large proteoglycan whose best-characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesi ...

s, which are not known to be protease inhibitors. In animals, serine protease inhibitors that act via their Kazal domain are grouped under 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 inhibito ...

inhibitor family I1, clan IA.

Kazal 1

Kazal domains often occur in tandem arrays. Small alpha+beta fold containing three

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. Alignment also includes a single domain from transporters in the OATP/PGT family .

Peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

proteinase inhibitors can be found as single

domain A domain is a geographic area controlled by a single person or organization. Domain may also refer to: Law and human geography * Demesne, in English common law and other Medieval European contexts, lands directly managed by their holder rather ...

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 ...

s or as single or multiple domains within proteins; these are referred to as either simple or compound inhibitors, respectively. In many cases they are synthesised as part of a larger

precursor Precursor or Precursors may refer to: *Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), hypothesized genus of fossil birds that was composed of fossilized parts of unre ...

protein, either as a prepropeptide or as an N-terminal domain associated with an inactive

peptidase A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do ...

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 ...

. This domain prevents access of the

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

to the

active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding s ...

. Removal of the N-terminal inhibitor domain either by interaction with a second peptidase or by

autocatalytic In chemistry, a chemical reaction is said to be autocatalytic if one of the reaction products is also a catalyst for the same reaction. Many forms of autocatalysis are recognized.Steinfeld J.I., Francisco J.S. and Hase W.L. ''Chemical Kinetics and ...

cleavage Cleavage may refer to: Science * Cleavage (crystal), the way in which a crystal or mineral tends to split * Cleavage (embryo), the division of cells in an early embryo * Cleavage (geology), foliation of rock perpendicular to stress, a result of ...

activates the zymogen. Other inhibitors

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...

direct with

proteinase A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do ...

s using a simple noncovalent lock and key mechanism; while yet others use a conformational change-based trapping

mechanism Mechanism may refer to: *Mechanism (economics), a set of rules for a game designed to achieve a certain outcome **Mechanism design, the study of such mechanisms *Mechanism (engineering), rigid bodies connected by joints in order to accomplish a ...

that depends on their

structural A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

and

thermodynamic Thermodynamics is a branch of physics that deals with heat, work, and temperature, and their relation to energy, entropy, and the physical properties of matter and radiation. The behavior of these quantities is governed by the four laws of th ...

properties. This family of Kazal inhibitors, belongs to MEROPS inhibitor family I1, clan IA. They

inhibit 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 ...

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

peptidases of the S1 family
INTERPRO
. The members are primarily metazoan, but includes exceptions in the alveolata (apicomplexa), stramenopiles,

higher plants Vascular plants (), also called tracheophytes (, ) or collectively tracheophyta (; ), are plants that have lignified tissues (the xylem) for conducting water and minerals throughout the plant. They also have a specialized non-lignified tissue ( ...

and

bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

. Kazal inhibitors, which inhibit a number of serine proteases (such as trypsin and elastase), belong to family of proteins that includes pancreatic secretory

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 ...

inhibitor; avian ovomucoid; acrosin inhibitor; and elastase inhibitor. These

s contain between 1 and 7 Kazal-type inhibitor

repeat Repeat may refer to: * Rerun, a rebroadcast of an episode of a radio or television program * Repeated sequence (DNA), a pattern of nucleic acid (DNA or RNA) that occurs in multiple copies throughout the genome ** CRISPR * The smallest rectangle th ...

s. The

structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

of the Kazal repeat includes a large quantity of extended chain, 2 short

alpha-helices An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

and a 3-stranded anti-parallel

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 gene ...

. The inhibitor makes 11 contacts with its

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

substrate: unusually, 8 of these important residues are hypervariable. Altering the enzyme-contact residues, and especially that of the active site bond, affects the strength of inhibition and specificity of the inhibitor for particular serine

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...

s. The presence of this Pfam domain is usually indicative of serine

inhibitors, however, Kazal-like domains are also seen in the

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

part of agrins which are not known to be proteinase inhibitors. Human proteins with Kazal 1 domains: * ''

AGRIN Agrin is a large proteoglycan whose best-characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesi ...

'', '' CPAMD8'' * '' FST'', '' FSTL3'', '' FSTL4'', '' FSTL5'' * '' IGFBPL1'' * '' SMOC1'', '' SPARC'', '' SPARCL1'', ''

SPINK1 Pancreatic secretory trypsin inhibitor (PSTI) also known as serine protease inhibitor Kazal-type 1 (SPINK1) or tumor-associated trypsin inhibitor (TATI) is a protein that in humans is encoded by the ''SPINK1'' gene. Mutations in SPINK1 has been a ...

'', '' SPINK2'', '' SPINK4'', ''

SPINK5 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 ...

'', '' SPINK5L2'', '' SPINK5L3'', ''

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 memb ...

'', '' SPINK7'', ''

SPINK9 Lympho-epithelial Kazal-type related inhibitor 2 (LEKTI-2) is a protein encoded by the ''SPINK9'' gene in humans. ''SPINK9'' is a member of a gene family cluster located on chromosome 5q33.1, which includes ''SPINK5'' and ''SPINK6''. LEKTI-2 is an ...

'' * '' TMEFF1'', '' TMEFF2''

Kazal 2

This

is usually indicative of serine protease

s that belong to Merops

families: I1, I2, I17 and I31. However, kazal-like domains are also seen in the

part of agrins, which are not known to be protease inhibitors. Kazal domains often occur in tandem arrays and have a central alpha-helix, a short two-stranded antiparallel

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 ...

and several disulphide

bond Bond or bonds may refer to: Common meanings * Bond (finance), a type of debt security * Bail bond, a commercial third-party guarantor of surety bonds in the United States * Fidelity bond, a type of insurance policy for employers * Chemical bond, t ...

s. The amino terminal segment of this domain

bind BIND () is a suite of software for interacting with the Domain Name System (DNS). Its most prominent component, named (pronounced ''name-dee'': , short for ''name Daemon (computing), daemon''), performs both of the main DNS server roles, acting ...

s to the

of its target proteases, thus inhibiting their function. Human proteins with Kazal 2 domains: * '' C6'', '' CFI'' * ''

FSTL1 Follistatin-related protein 1 is a protein that in humans is encoded by the ''FSTL1'' gene. Structure This gene encodes a protein with similarity to follistatin, an BMP-4-binding protein. It binds to BMP-4 and TGF-β1, but not Activin A. It c ...

'', '' FSTL3'' * '' HTRA1'', '' HTRA3'', '' HTRA4'' * ''

IGFBP7 Insulin-like growth factor-binding protein 7 is a protein that in humans is encoded by the ''IGFBP7'' gene. The major function of the protein is the regulation of availability of insulin-like growth factors (IGFs) in tissue as well as in modulat ...

'', '' KAZALD1'', '' LST3'', ''

RECK Reck or Rek is a surname of German origin. People with the surname * Friedrich Reck (1884-1945), German author and opponent of Nazism * John Reck (1865–1951), American politician * Hans Reck (1886–1937), German volcanologist and paleontolo ...

'' * '' SLC21A8'', ''

SLCO1A2 Solute carrier organic anion transporter family member 1A2 is a protein that in humans is encoded by the ''SLCO1A2'' gene. This gene encodes a sodium-independent transporter which mediates cellular uptake of organic ions in the liver. Its substrat ...

'', ''

SLCO1B1 Solute carrier organic anion transporter family member 1B1 is a protein that in humans is encoded by the ''SLCO1B1'' gene. Pharmacogenomic research indicates that genetic variations in this gene are associated with response to simvastatin. Clini ...

'', ''

SLCO1B3 Solute carrier organic anion transporter family member 1B3 (SLCO1B3) also known as organic anion-transporting polypeptide 1B3 (OATP1B3) is a protein that in humans is encoded by the ''SLCO1B3'' gene. OATP1B3 is a 12-transmembrane domain influx tr ...

'', ''

SLCO1C1 Members of the Organic Anion Transporter (OAT) Family (organic-anion-transporting polypeptides, OATP) are membrane transport proteins or 'transporters' that mediate the transport of mainly organic anions across the cell membrane. Therefore, OATPs ...

'', ''

SLCO2A1 Solute carrier organic anion transporter family member 2A1, also known as the prostaglandin transporter (PGT), is a protein that in humans is encoded by the SLCO2A1 gene. This gene encodes a prostaglandin transporter that is a member of the 12-m ...

'', ''

SLCO3A1 Solute carrier organic anion transporter family member 3A1 is a protein that in humans is encoded by the ''SLCO3A1'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a se ...

'', ''

SLCO4A1 Solute carrier organic anion transporter family member 4A1 is a protein that in humans is encoded by the ''SLCO4A1'' gene. See also * Solute carrier family The solute carrier (SLC) group of membrane transport proteins include over 400 members or ...

'', '' SLCO4C1'', '' SLCO5A1'', '' SLCO6A1'', '' SMOC2'', ''

'', '' SPOCK1'', '' SPOCK2'', '' SPOCK3'' * ''

WFIKKN1 WAP, kazal, immunoglobulin, kunitz and NTR domain-containing protein 1 is a protein that is encoded by the ''WFIKKN1'' gene. when found in humans. This gene encodes a secreted multidomain protein consisting of a signal peptide, a WAP domain, a f ...

'', '' WFIKKN2''

References

{{InterPro content, IPR011497 Protein domains Serine protease inhibitors