Granzyme B (GrB) is one of the
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. ...
granzyme Granzymes are serine proteases released by cytoplasmic granules within cytotoxic T cells and natural killer (NK) cells. They induce programmed cell death (apoptosis) in the target cell, thus eliminating cells that have become cancerous or are infec ...
s most commonly found in the granules of
natural killer cells
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
(NK cells) and
cytotoxic T cells
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
. It is secreted by these cells along with the pore forming protein
perforin
Perforin-1 is a protein that in humans is encoded by the ''PRF1'' gene and the ''Prf1'' gene in mice.
Function
Perforin is a pore forming cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and natural killer cells (NK ce ...
to mediate
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
in target cells.
Granzyme B has also been found to be produced by a wide range of non-cytotoxic cells ranging from
basophils
Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammat ...
and
mast cells
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...
to
smooth muscle cells
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
.
The secondary functions of granzyme B are also numerous. Granzyme B has shown to be involved in inducing
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
by stimulating
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
release and is also involved in
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
remodelling.
Elevated levels of granzyme B are also implicated in a number of
autoimmune diseases
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
, several skin diseases, and
type 1 diabetes
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...
.
Structure
In humans, granzyme B is encoded by ''GZMB'' on chromosome 14q.11.2, which is 3.2kb long and consists of 5
exons
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
.
It is one of the most abundant granzymes of which there are 5 in humans and 10 in mice.
Granzyme B is thought to have evolved from a
granzyme H related precursor and is more effective at lower concentrations than the other granzymes.
The enzyme is initially in an inactive precursor
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 active ...
form, with an additional
amino terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
peptide sequence.
This sequence can be cleaved by
cathepsin C
Cathepsin C (CTSC) also known as dipeptidyl peptidase I (DPP-I) is a lysosomal exo-cysteine protease belonging to the peptidase C1 protein family, a subgroup of the cysteine cathepsins. In humans, it is encoded by the ''CTSC'' gene.
Function ...
, removing 2
amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
.
Cathepsin H
Cathepsin H is a protein that in humans is encoded by the ''CTSH'' gene.
The protein encoded by this gene is a cysteine cathepsin, a lysosomal cysteine protease important in the overall degradation of lysosomal proteins. It is composed of a dime ...
has also been reported to activate granzyme B.
Granzyme B's structure consists of two 6 stranded
β sheets
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 g ...
with 3 trans domain segments. In the granules of cytotoxic lymphocytes the enzyme can exist in two
glycosylated
Glycosylation is the reaction in which a carbohydrate (or 'glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not alw ...
forms. The high mannose form weighs 32kDa and the complex form, 35kDa.
Granzyme B contains the
catalytic triad
A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes (e.g. proteases, amidases, esterases, acylases, lip ...
histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...
-
aspartic acid
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
-
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 − form un ...
in its
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 (binding site) a ...
and preferentially cleaves after an
aspartic acid
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
residue situated in the P1 position. The aspartic acid residue to be cleaved associates with 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 ...
residue in the enzyme's binding pocket.
Granzyme B is active at a neutral
pH and is therefore inactive in the acidic CTL granules. The enzyme is also rendered inactive when bound by
serglycin in the granules to avoid apoptosis triggering inside the cytotoxic T cells themselves.
Delivery
Granzyme B is released with perforin which inserts into a target cell's
plasma membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
forming a
pore
Pore may refer to:
Biology Animal biology and microbiology
* Sweat pore, an anatomical structure of the skin of humans (and other mammals) used for secretion of sweat
* Hair follicle, an anatomical structure of the skin of humans (and other m ...
. Perforin has a radius of 5.5 nm and granzyme B has a
stokes radius
The Stokes radius or Stokes–Einstein radius of a solute is the radius of a hard sphere that diffuses at the same rate as that solute. Named after George Gabriel Stokes, it is closely related to solute mobility, factoring in not only size but also ...
of 2.5 nm and can therefore pass through the perforin pore into the target to be destroyed.
Alternatively, once released, granzyme B can bind to negatively charged
heparan sulphate
Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ...
containing receptors on a target cell and become
endocytosed. The
vesicles
Vesicle may refer to:
; In cellular biology or chemistry
* Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane
* Synaptic vesicle
; In human embryology
* Vesicle (embryology), bulge-like features o ...
that carry the enzyme inside then burst, exposing granzyme b to the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
and its
substrates.
Hsp-70 has also been linked to aiding granzyme B entry.
Granzyme B has also been proposed to enter a target by first exchanging its bound serglycin for negative
phospholipids
Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
in a target's plasma membrane. Entry then occurs by the less selective process of
absorptive pinocytosis.
Mediated apoptosis
Once inside the target cell, granzyme B can cleave and activate initiator caspases
8 and
10, and executioner caspases
3 and
7 which trigger apoptosis.
Caspase 7 is the most sensitive to granzyme B and caspases 3, 8, and 10 are only cleaved to intermediate fragments and need further cleavage for full activation.
Granzyme B can also cleave
BID leading to
BAX/
BAK oligomerisation
In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relative ...
and
cytochrome c
The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...
release from the
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
. Granzyme B can cleave
ICAD leading to DNA fragmentation and the
laddering pattern associated with apoptosis.
Granzyme B has a potential of over 300 substrates and can cleave
Mcl-1
Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the ''MCL1'' gene.
Function
The protein encoded by this gene belongs to the Bcl-2 family. Alternative splicing occurs at this locus and two tr ...
in the
outer mitochondrial membrane
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used t ...
relieving its inhibition of
Bim
''Bim'' is a 1974 Trinidad and Tobago film written by Raoul Pantin and directed by Hugh A. Robertson. It was described by Bruce Paddington as "one of the most important films to be produced in Trinidad and Tobago and... one of the classics of Ca ...
. Bim stimulates BAX/BAK oligomerisation, mitochondrial membrane permeability and apoptosis. Granzyme B can also cleave
HAX1 (Hs-1 associated protein X-1) to facilitate mitochondria polarisation.
Granzyme B can also generate a cytotoxic level of mitochondrial
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(ROS) to mediate cell death.
The caspase independent pathways of cell death are thought to have arisen to overcome
viruses
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
that can inhibit caspases and prevent apoptosis.
Targets
Nucleus
Granzyme B has many substrates located in the
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucle ...
. Granzyme B can cleave
PARP (poly ADP ribose polymerase) and
DNA PK (DNA protein kinase) to disrupt DNA repair and
retroviral
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase e ...
DNA integration. Granzyme B can also cleave
nucleophosmin
Nucleophosmin (NPM), also known as nucleolar phosphoprotein B23 or numatrin, is a protein that in humans is encoded by the ''NPM1'' gene.
Function
NPM1 is associated with Nucleolus, nucleolar ribonucleoprotein structures and binds single-stra ...
,
topoisomerase 1
In molecular biology Type I topoisomerases are enzymes that cut one of the two strands of double-stranded DNA, relax the strand, and reanneal the strand. They are further subdivided into two structurally and mechanistically distinct topoisomeras ...
and
nucleolin
Nucleolin is a protein that in humans is encoded by the ''NCL'' gene.
Gene
The human NCL gene is located on chromosome 2 and consists of 14 exons with 13 introns and spans approximately 11kb. The intron 11 of the NCL gene encodes a small nucle ...
to prevent viral replication.
Granzyme B can cleave ICP4 from the
HSV 1
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...
virus which is an essential protein used for gene
transactivation In the context of gene regulation: transactivation is the increased rate of gene expression triggered either by biological processes or by artificial means, through the expression of an intermediate transactivator protein.
In the context of recep ...
and
NUMA
Nuclear mitotic apparatus protein 1 is a protein that in humans is encoded by the ''NUMA1'' gene.
Interactions
Nuclear mitotic apparatus protein 1 has been shown to interact with PIM1, Band 4.1, GPSM2 and EPB41L1
Band 4.1-like protein 1 is a pro ...
(Nuclear mitotic apparatus protein) can be cleaved to prevent
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
.
Granzyme B can also cleave
DBP (DNA Binding Protein) into a 50 kDa fragment and then into an additional 60 kDa indirectly through the caspases it activates.
Extracellular matrix
Granzyme B can degrade many proteins in the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
(ECM) including
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
,
vitronectin
Vitronectin (VTN or VN) is a glycoprotein of the hemopexin family which is abundantly found in serum, the extracellular matrix and bone. In humans it is encoded by the ''VTN'' gene.
Vitronectin binds to integrin alpha-V beta-3 and thus promotes c ...
and
aggrecan
Aggrecan (ACAN), also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ''ACAN'' gene. This gene is a member of the lectican (chondroitin sulfate prote ...
. Cleavage can cause cell death by
anoikis Anoikis is a form of programmed cell death that occurs in anchorage-dependent cells when they detach from the surrounding extracellular matrix (ECM). Usually cells stay close to the tissue to which they belong since the communication between proxima ...
and release alarmins from the ECM inducing inflammation.
Fragments of fibronectin can attract
neutrophils
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
and stimulate
MMP expression from
chondrocytes
Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...
.
Basophils secrete granzyme B to degrade
endothelial
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
cell-cell contacts allowing
extravasation
__NOTOC__
Extravasation is the leakage of a fluid out of its container into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells from the capillaries to the ...
to sites of inflammation.
Granzyme B can also induce inflammation by processing cytokines
IL-1α
Interleukin-1 alpha (IL-1 alpha) also known as hematopoietin 1 is a cytokine of the interleukin 1 family that in humans is encoded by the ''IL1A'' gene. In general, Interleukin 1 is responsible for the production of inflammation, as well as the p ...
and
IL18. It can also trigger the release of
IL6 and
IL8 through activation of
PAR1 (Protease activated receptor 1).
Cleavage of vitronectin occurs at the RGD
integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
binding site interrupting cell growth signalling pathways. Cleavage of
laminin
Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...
and fibronectin disrupts
dermal-epidermal junction attachment and cross talk while decorin destruction by granzyme B causes
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
disorganisation, skin thinning and aging.
Keratinocytes
Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells.
Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referred ...
can express granzyme B after exposure to
UVA
UVA most often refers to:
* Ultraviolet A, a type of ultraviolet radiation
* University of Virginia, a public research university in Charlottesville, Virginia, United States
Uva or UVA may also refer to:
Places
* Uva, Missouri, an unincorpora ...
and
UVB
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation i ...
which is linked to
photoaging
Photoaging or photoageing (also known as "dermatoheliosis") is a term used for the characteristic changes to skin induced by chronic UVA and UVB exposure. Tretinoin is the best studied retinoid in the treatment of photoaging.
The deterioration ...
of the skin.
Granzyme B can also impair wound healing. Cleavage of the
von Willebrand factor
Von Willebrand factor (VWF) () is a blood glycoprotein involved in hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thrombocytopen ...
inhibits
platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
aggregation and of
plasminogen
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 ...
produces an
angiostatin Angiostatin is a naturally occurring protein found in several animal species, including humans. It is an endogenous angiogenesis inhibitor (i.e., it blocks the growth of new blood vessels). Clinical trials have been undertaken for its use in antica ...
fragment preventing
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
. The cutting of fibronectins and vitronectins delays the formation of a provisional matrix impairing wound healing further.
T cell regulation
Granzyme B is secreted by
regulatory T cells
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosup ...
(tregs) to kill
CD4
In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ...
+ T cells that have not been exposed to host cells that are restricted to the peripheral tissues and cannot reach the
thymus
The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...
. This
activation-induced cell death (AICD)
AICD (activation-induced cell death) is programmed cell death caused by the interaction of Fas receptors (Fas, CD95) and Fas ligands (FasL, CD95 ligand).Zhang J, Xu X, Liu Y. (2004), Activation-Induced Cell Death in T Cells and Autoimmunity. Cell ...
can be achieved without the
Fas death pathway and prevents
autoimmune reaction
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
to
self antigens.
Inhibitors
Granzyme B's most common inhibitor is
SERPINB9
Serpin B9 is a protein that in humans is encoded by the ''SERPINB9'' gene.
PI9 belongs to the large superfamily of serine proteinase inhibitors (serpins), which bind to and inactivate serine proteinases. These interactions are involved in many cel ...
also known as proteinase inhibitor nine (PI-9) which is 376 amino acids long and found in the nucleus and cytoplasm.
It is produced by many types of cell to protect themselves from accidental granzyme B mediated cell death. PI-9 is
metastable
In chemistry and physics, metastability denotes an intermediate Energy level, energetic state within a dynamical system other than the system's ground state, state of least energy.
A ball resting in a hollow on a slope is a simple example of me ...
and forms an energetically favourable conformation when bound to granzyme B. The reactive loop centre (RCL) of the PI-9 molecule acts as a pseudosubstrate and initially forms a reversible Michaelis complex. Once the
peptide bond
In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide or protein cha ...
of the RCL is cleaved between positions P1 and P1', granzyme B is permanently inhibited.
However, if the RCL is cleaved efficiently, PI-9 does not act as a 1:1
suicide substrate
In biochemistry, suicide inhibition, also known as suicide inactivation or mechanism-based inhibition, is an irreversible form of enzyme inhibition that occurs when an enzyme binds a substrate analog and forms an irreversible complex with it thr ...
and granzyme B is left uninhibited.
Granzyme M can also cleave PI-9 in the nucleus and cytoplasm to relieve granzyme B of inhibition.
Protein L4-100K from
adenoviruses
Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from thei ...
can also inhibit granzyme B by binding at
exosites and specific binding pockets.
L4-100K is an assembly protein that can transport
hexon capsomeres into the nucleus of an adenovirus. 100k can be cleaved to a 90kDa fragment by
granzyme H to relieve this inhibition which is important in adenovirus 5 infected cells.
Role in disease
Granzyme B has a normal concentration of 20-40 pg/ml in the
blood plasma
Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intra ...
while retaining 70% activity and elevated concentrations of granzyme B are found in a number of disease states.
Granzyme B can generate autoantigens by cleaving in disordered regions and linker regions of antigens exposing new
epitopes
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...
and this can cause the development of autoimmune diseases.
Granzyme B release with perforin from
CD8+ T cells can cause
heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
and
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
transplant rejection
Transplant rejection occurs when Organ transplant, transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between don ...
through killing of allogeneic endothelial cells. The destruction of
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
producing
β cells in
pancreatic islets
The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of ...
is mediated by T cells and granzyme B contributing to Type 1 Diabetes. Granzyme B can also mediate the death of cells after
spinal cord injury
A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. Symptoms may include loss of muscle function, sensation, or autonomic function in the parts of the body served by the spinal cor ...
and is found at elevated levels in
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
.
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...
(COPD) has been attributed to granzyme B secreted from NK and T cells causing the apoptosis of
bronchial epithelial cells. Matrix destabilisation and remodelling by granzyme B is also linked to
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
pathogenesis.
Granzyme B can kill
melanocytes
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and heart.
...
causing the skin condition
vitiligo
Vitiligo is a disorder that causes the skin to lose its color. Specific causes are unknown but studies suggest a link to immune system changes.
Signs and symptoms
The only sign of vitiligo is the presence of pale patchy areas of depigmen ...
and granzyme B overexpression is found in
contact dermatitis
Contact dermatitis is a type of acute or chronic inflammation of the skin caused by exposure to chemical or physical agents. Symptoms of contact dermatitis can include itchy or dry skin, a red rash, bumps, blisters, or swelling. These rashes are ...
,
lichen sclerosus
Lichen sclerosus (LS) is a chronic, inflammatory skin disease of unknown cause which can affect any body part of any person but has a strong preference for the genitals (penis, vulva) and is also known as balanitis xerotica obliterans (BXO) when ...
and
lichen planus
Lichen planus (LP) is a chronic inflammatory and immune-mediated disease that affects the skin, nails, hair, and mucous membranes. It is not an actual lichen, and is only named that because it looks like one. It is characterized by polygonal, fla ...
cases.
Cytotoxic cells expressing granzyme B have been identified close to
hair follicles
The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between h ...
linking a possible role in hair loss.
The ECM remodelling properties of granzyme B have also implicated its involvement in
left ventricular remodelling, which increases the subsequent chances of
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
. The weakening of the
fibrous cap The fibrous cap is a layer of fibrous connective tissue, which is thicker and less cellular than the normal intima, found in atherosclerotic plaques. The fibrous cap contains macrophages and smooth muscle cells.
The fibrous cap of an atheroma is c ...
of
atheromatous plaques by apoptosis of smooth muscle cells has also been linked to granzyme B.
References
External links
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EC 3.4.21