Kazal-type serine protease inhibitor domain
Encyclopedia
Kazal-type serine protease inhibitor domain is an evolutionary conserved protein domain
.
Usually indicative of serine protease
inhibitor
s. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors.
s. Alignment also includes a single domain from transporters in the OATP/PGT family .
Peptide
proteinase inhibitors
can be found as single domain
protein
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
protein, either as a prepropeptide or as an N-terminal domain associated with an inactive peptidase or zymogen
. This domain prevents access of the substrate to the active site
. Removal of the N-terminal inhibitor domain either by interaction with a second peptidase or by autocatalytic cleavage
activates the zymogen. Other inhibitors interact
direct with proteinases using a simple noncovalent lock and key mechanism; while yet others use a conformational
change-based trapping mechanism that depends on their structural
and thermodynamic properties.
This family of Kazal inhibitors, belongs to MEROPS inhibitor family I1, clan IA. They inhibit
serine
peptidases of the S1 family (INTERPRO). The members are primarily metazoan, but includes exceptions in the alveolata (apicomplexa), stramenopiles, higher plants and bacteria
.
Kazal inhibitors, which inhibit a number of serine proteases (such as trypsin and elastase), belong to family of proteins
that includes pancreatic secretory trypsin
inhibitor; avian ovomucoid; acrosin inhibitor; and elastase inhibitor. These protein
s contain between 1 and 7 Kazal-type inhibitor repeat
s.
The structure
of the Kazal repeat includes a large quantity of extended chain, 2 short alpha-helices
and a 3-stranded anti-parallel beta sheet
. The inhibitor makes 11 contacts with its enzyme
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
s. The presence of this Pfam domain is 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 proteinase inhibitors.
is usually indicative of serine protease inhibitor
s that belong to Merops inhibitor
families: I1, I2, I17 and I31. However, kazal-like domains
are also seen in the extracellular
part of agrins, which are not known to be protease inhibitor
s. Kazal domains often occur in tandem arrays
and have a central alpha-helix, a short two-stranded antiparallel
beta-sheet and several disulphide bond
s. The amino terminal segment of this domain binds to the active site
of its target proteases, thus inhibiting their function.
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
.
Usually indicative of 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...
s. 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 occur in tandem arrays. Small alpha+beta fold containing three disulfide bondDisulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
s. Alignment also includes a single domain from transporters in the OATP/PGT family .
Peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
proteinase inhibitors
Protease inhibitor (biology)
In biology and biochemistry, protease inhibitors are molecules that inhibit the function of proteases. Many naturally occurring protease inhibitors are proteins....
can be found as single domain
Domain (biology)
In biological taxonomy, a domain is the highest taxonomic rank of organisms, higher than a kingdom. According to the three-domain system of Carl Woese, introduced in 1990, the Tree of Life consists of three domains: Archaea, Bacteria and Eukarya...
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...
s or as single or multiple domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
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
Protein precursor
A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein that can be turned into an active form by posttranslational modification. The name of the precursor for a protein is often prefixed by pro...
protein, either as a prepropeptide or as an N-terminal domain associated with an inactive peptidase or zymogen
Zymogen
A zymogen is an inactive enzyme precursor. A zymogen requires a biochemical change for it to become an active enzyme. The biochemical change usually occurs in a lysosome where a specific part of the precursor enzyme is cleaved in order to activate it...
. This domain prevents access of the substrate to the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
. Removal of the N-terminal inhibitor domain either by interaction with a second peptidase or by autocatalytic cleavage
Cleavage
Cleavage may refer to:*Cleavage , partial exposure of the separation between a woman's breasts.**Cleavage enhancement, methods of making a person's breast cleavage look more substantial than it really is....
activates the zymogen. Other inhibitors interact
Protein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
direct with proteinases using a simple noncovalent lock and key mechanism; while yet others use a conformational
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
change-based trapping mechanism that depends on their structural
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
and thermodynamic properties.
This family of Kazal inhibitors, belongs to MEROPS inhibitor family I1, clan IA. They inhibit
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...
serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
peptidases of the S1 family (INTERPRO). The members are primarily metazoan, but includes exceptions in the alveolata (apicomplexa), stramenopiles, higher plants and bacteria
Zinc dependent phospholipase C
Zinc-dependent prokaryotic phospholipases C is a family of bacterial phospholipases C, some of which are also known as alpha toxins.Bacillus cereus contains a monomeric phospholipase C of 245 amino-acid residues. Although PLC prefers to acton phosphatidylcholine, it also shows weak catalytic...
.
Kazal inhibitors, which inhibit a number of serine proteases (such as trypsin and elastase), belong to family of proteins
Protein family
A protein family is a group of evolutionarily-related proteins, and is often nearly synonymous with gene family. The term protein family should not be confused with family as it is used in taxonomy....
that includes pancreatic secretory 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...
inhibitor; avian ovomucoid; acrosin inhibitor; and elastase inhibitor. These 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...
s contain between 1 and 7 Kazal-type inhibitor repeat
Tandem repeat
Tandem repeats occur in DNA when a pattern of two or more nucleotides is repeated and the repetitions are directly adjacent to each other. -Example:An example would be:in which the sequence A-T-T-C-G is repeated three times.-Terminology:...
s.
The structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
of the Kazal repeat includes a large quantity of extended chain, 2 short alpha-helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
and a 3-stranded anti-parallel beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
. The inhibitor makes 11 contacts with its enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
substrate: unusually, 8 of these important residues
Residue (chemistry)
In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....
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
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s. The presence of this Pfam domain is usually indicative of serine protease
HIV-1 protease
HIV-1 protease is a retroviral aspartyl protease that is essential for the life-cycle of HIV, the retrovirus that causes AIDS.HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion...
inhibitors, however, Kazal-like domains are also seen in the extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
part of agrins which are not known to be proteinase inhibitors.
Kazal_2
This domainDomain (biology)
In biological taxonomy, a domain is the highest taxonomic rank of organisms, higher than a kingdom. According to the three-domain system of Carl Woese, introduced in 1990, the Tree of Life consists of three domains: Archaea, Bacteria and Eukarya...
is usually indicative of serine protease 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...
s that belong to Merops 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...
families: I1, I2, I17 and I31. However, kazal-like domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
are also seen in the extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
part of agrins, which are not known to be protease inhibitor
Protease inhibitor (biology)
In biology and biochemistry, protease inhibitors are molecules that inhibit the function of proteases. Many naturally occurring protease inhibitors are proteins....
s. Kazal domains often occur in tandem arrays
Tandemly arrayed genes
Tandemly arrayed genes are a gene cluster created by tandem duplications. They serve to encode large numbers of genes at a time. An example are tandem clusters of rRNA encoding genes. These genes are translated faster than they would be if only a single copy of the gene was available.-See also:*...
and have a central alpha-helix, a short two-stranded antiparallel
Antiparallel (biochemistry)
In biochemistry, two molecules are antiparallel if they run side-by-side in opposite directions or when both strands are complimentary to each other....
beta-sheet and several disulphide bond
Chemical bond
A chemical bond is an attraction between atoms that allows the formation of chemical substances that contain two or more atoms. The bond is caused by the electromagnetic force attraction between opposite charges, either between electrons and nuclei, or as the result of a dipole attraction...
s. The amino terminal segment of this domain binds to the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
of its target proteases, thus inhibiting their function.
Kazal_1
- AGRINAgrinAgrin 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 synaptogenesis. In humans, this protein is encoded by the AGRN...
, CPAMD8 - FSTFollistatinFollistatin also known as activin-binding protein is a protein that in humans is encoded by the FST gene. Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals....
, FSTL3FSTL3Follistatin-related protein 3 is a protein that in humans is encoded by the FSTL3 gene.-Further reading:...
, FSTL4, FSTL5 - IGFBPL1
- SMOC1, SPARCSPARCSPARC is a RISC instruction set architecture developed by Sun Microsystems and introduced in mid-1987....
, SPARCL1SPARCL1SPARC-like protein 1 is a protein that in humans is encoded by the SPARCL1 gene.-Further reading:...
, SPINK1SPINK1Pancreatic secretory trypsin inhibitor also known as serine protease inhibitor Kazal-type 1 or tumor-associated trypsin inhibitor is a protein that in humans is encoded by the SPINK1 gene....
, SPINK2SPINK2Serine protease inhibitor Kazal-type 2 also known as acrosin-trypsin inhibitor is a protein that in humans is encoded by the SPINK2 gene....
, SPINK4, SPINK5SPINK5Lympho-epithelial Kazal-type-related inhibitor also known as serine protease inhibitor Kazal-type 5 is a protein that in humans is encoded by the SPINK5 gene.- Structure and function :...
, SPINK5L2, SPINK5L3, SPINK6SPINK6Serine 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...
, SPINK7, SPINK9 - TMEFF1, TMEFF2TMEFF2Tomoregulin-2 is a protein that in humans is encoded by the TMEFF2 gene.-Further reading:...
Kazal_2
- C6Complement component 6Complement component 6 is a protein that in humans is encoded by the C6 gene.Complement component 6 is a protein involved in the complement system. It is part of the membrane attack complex which can insert into the cell membrane and cause cell to lyse....
, CFIComplement factor IComplement factor I, also known as C3B/C4B inactivator, is a protein that in humans is encoded by the CFI gene.Complement Factor I is a protein of the complement system, first isolated in 1966 in guinea pig serum that regulates complement activation by cleaving cell-bound or fluid phase C3b and... - FSTL1FSTL1Follistatin-related protein 1 is a protein that in humans is encoded by the FSTL1 gene.-Further reading:...
, FSTL3FSTL3Follistatin-related protein 3 is a protein that in humans is encoded by the FSTL3 gene.-Further reading:... - HTRA1HTRA1Serine protease HTRA1 is an enzyme that in humans is encoded by the HTRA1 gene. The HTRA1 protein is composed of four distinct protein domains. They are from amino-terminus to carboxyl-terminus an Insulin-like growth factor binding domain, a kazal domain, a trypsin-like peptidase domain and a PDZ...
, HTRA3, HTRA4 - IGFBP7IGFBP7Insulin-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 in tissue as well as in modulating IGF binding to its receptors. IGFBP7 binds to IGF with high...
, KAZALD1KAZALD1Kazal-type serine protease inhibitor domain-containing protein 1 is an enzyme that in humans is encoded by the KAZALD1 gene.-Further reading:...
, LST3, RECKRECKReversion-inducing-cysteine-rich protein with kazal motifs, also known as RECK, is a human gene, thought to be a metastasis suppressor.-Further reading:... - SLC21A8, SLCO1A2SLCO1A2Solute carrier organic anion transporter family member 1A2 is a protein that in humans is encoded by the SLCO1A2 gene.-Further reading:...
, SLCO1B1SLCO1B1Solute carrier organic anion transporter family member 1B1 is a protein that in humans is encoded by the SLCO1B1 gene.-Further reading:...
, SLCO1B3SLCO1B3Solute carrier organic anion transporter family member 1B3 also known as organic anion-transporting polypeptide 1B3 is a protein that in humans is encoded by the SLCO1B3 gene....
, SLCO1C1, SLCO2A1, SLCO3A1SLCO3A1Solute carrier organic anion transporter family member 3A1 is a protein that in humans is encoded by the SLCO3A1 gene.-Further reading:...
, SLCO4A1SLCO4A1Solute carrier organic anion transporter family member 4A1 is a protein that in humans is encoded by the SLCO4A1 gene.-Further reading:...
, SLCO4C1, SLCO5A1, SLCO6A1, SMOC2SMOC2SPARC-related modular calcium-binding protein 2 is a protein that in humans is encoded by the SMOC2 gene.-Further reading:...
, SPINK5SPINK5Lympho-epithelial Kazal-type-related inhibitor also known as serine protease inhibitor Kazal-type 5 is a protein that in humans is encoded by the SPINK5 gene.- Structure and function :...
, SPOCK1SPOCK1Testican-1 is a protein that in humans is encoded by the SPOCK1 gene.-Further reading:...
, SPOCK2SPOCK2Testican-2 is a protein that in humans is encoded by the SPOCK2 gene.-Further reading:...
, SPOCK3 - WFIKKN1WFIKKN1WAP, kazal, immunoglobulin, kunitz and NTR domain-containing protein 1 is a protein that in humans is encoded by the WFIKKN1 gene.-Further reading:...
, WFIKKN2