Calprotectin is a
complex
Complex commonly refers to:
* Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe
** Complex system, a system composed of many components which may interact with each ...
of the
mammal
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
ian proteins
S100A8
S100 calcium-binding protein A8 (S100A8) is a protein that in humans is encoded by the ''S100A8'' gene. It is also known as calgranulin A.
The proteins S100A8 and S100A9 form a heterodimer called calprotectin
Calprotectin is a multiprotein co ...
and
S100A9
S100 calcium-binding protein A9 (S100A9) also known as migration inhibitory factor-related protein 14 (MRP14) or calgranulin B is a protein that in humans is encoded by the ''S100A9'' gene.
The proteins S100A8 and S100A9 form a heterodimer calle ...
.
Other names
Other often refers to:
* Other (philosophy), a concept in psychology and philosophy
Other or The Other may also refer to:
Film and television
* ''The Other'' (1913 film), a German silent film directed by Max Mack
* ''The Other'' (1930 film), ...
for calprotectin include MRP8-MRP14,
calgranulin
Calgranulin is an S100 calcium-binding protein that is expressed in multiple cell types, including renal epithelial cells and neutrophils.
The proteins S100A8 and S100A9 form a heterodimer called calprotectin.
Human genes
* '' S100A8'' (calgr ...
A and B, cystic fibrosis antigen, L1, 60BB antigen, and 27E10 antigen.
The proteins exist as homodimers but preferentially exist as S100A8/A9 heterodimers or heterotetramers (calprotectin) with antimicrobial, proinflammatory and prothrombotic properties.
In the presence of
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
, calprotectin is capable of sequestering the transition metals
iron
Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...
,
manganese
Manganese is a chemical element with the symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese is a transition metal with a multifaceted array of industrial alloy use ...
and
zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
via
chelation
Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a Denticity, polydentate (multiple bonded) ligand and a single central metal atom. These l ...
.
This metal sequestration affords the complex
antimicrobial
An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals ar ...
properties.
Calprotectin is the only known antimicrobial manganese sequestration protein complex.
Calprotectin comprises as much as 60% of the soluble protein content of the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
of a
neutrophil
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 it is secreted by an unknown mechanism during
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 ...
.
Faecal calprotectin has been used to detect intestinal inflammation (
colitis
Colitis is swelling or inflammation of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases.
In a medical context, the label ''colitis'' (without qualification) ...
or
enteritis
Enteritis is inflammation of the small intestine. It is most commonly caused by food or drink contaminated with pathogenic microbes,Dugdale, David C., IIII, and George F Longretc"Enteritis" MedlinePlus Medical Encyclopedia, 18 October 2008. Access ...
) and can serve as a
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
for
inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...
s.
Blood based calprotectin (in
serum and
plasma
Plasma or plasm may refer to:
Science
* Plasma (physics), one of the four fundamental states of matter
* Plasma (mineral), a green translucent silica mineral
* Quark–gluon plasma, a state of matter in quantum chromodynamics
Biology
* Blood pla ...
) is used in diagnostics of multiple inflammatory diseases, including autoimmune diseases, like
arthritis
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
, and severe infections including
sepsis
Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...
.
Structure
![Calprotectin-4GGF](https://upload.wikimedia.org/wikipedia/commons/3/3f/Calprotectin-4GGF.png)
The human
homologue of calprotectin is a 24
kDa
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ...
,
and is formed by the protein monomers S100A8 (10,835 Da) and S100A9 (13,242 Da).
The
primary structure
Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthes ...
of calprotectin can vary between species. For instance, the mouse homologue of S100A8 is 10,295 Da,
while the S100A9 homologue is 13,049 Da.
Early
size exclusion chromatography
Size-exclusion chromatography (SEC), also known as molecular sieve chromatography, is a chromatographic method in which molecules in solution are separated by their size, and in some cases molecular weight. It is usually applied to large molecules ...
experiments incorrectly indicated that calprotectin had a molecular mass of 36.5 kDa;
occasionally this value is used in contemporary literature. Calprotectin S100A8-S100A9 dimers can
non-covalently pair with one another to form 48 kDa
tetramers
A tetramer () (''tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula Ti ...
.
Metal binding
Calprotectin has a high affinity for calcium, zinc, iron, and manganese.
Each of S100A8 and S100A9 contain two
EF-hand
The EF hand is a helix–loop–helix structural domain or ''motif'' found in a large family of calcium-binding proteins.
The EF-hand motif contains a helix–loop–helix topology, much like the spread thumb and forefinger of the human hand, in ...
type Ca
2+ binding sites,
and calprotectin is able to bind a total of four calcium ions per dimer or eight calcium ions per tetramer.
Calcium binding induces a
conformational change
In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors.
A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
in the complex that improves its affinity for
transition metals
In chemistry, a transition metal (or transition element) is a chemical element in the d-block of the periodic table (groups 3 to 12), though the elements of group 12 (and less often group 3) are sometimes excluded. They are the elements that can ...
, and promotes tetramer formation.
A maximum of two transition metal ions may bind to each calprotectin S100A8-S100A9 dimer.
A calprotectin dimer can bind only one manganese or iron ion with high affinity, and it can do this only in the presence of calcium.
Zinc can bind at two sites within the calprotectin dimer, and this can occur in the absence of calcium.
Calcium, however, improves calprotectin's affinity for zinc.
While calprotectin metal binding occurs at the interface of S100A9 and S100A8 monomers, the independent monomers have some capacity for zinc binding, and may contribute to zinc
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 ...
within mammals.
The first of the two calprotectin metal binding sites consists of a His
3Asp
motif, with S100A8 contributing two
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 ...
ligands (His83 and His87), and S100A9 contributing a histidine and 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 ...
ligand (His20 and Asp30).
The second site can coordinate metals through a tetra-histidine (His
4) or a hexa-histidine (His
6) binding motif. In the case of His
4 binding, S100A8 coordinates through both His17 and His27 while S100A9 coordinates through His91 and His95.
In hexa-histidine binding two further histidine residues, His103 and His105, are recruited from the
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
end of S100A9 to enable
octahedral coordination of the transition metal.
Manganese or iron are bound by the calprotectin dimer at this His
6 site.
Zinc can be bound to either of the sites that form at the interface between S100A8 and S100A9 monomers.
Inflammatory disease
Calprotectin constitutes up to 60% of soluble protein content in the cytosol of neutrophil granulocytes,
and it can be found at a lower concentration in
monocytes
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
,
macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
, and
squamous epithelial cell
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
s.
Calprotectin enters into
pus
Pus is an exudate, typically white-yellow, yellow, or yellow-brown, formed at the site of inflammation during bacterial or fungal infection. An accumulation of pus in an enclosed tissue space is known as an abscess, whereas a visible collection ...
and
abscess
An abscess is a collection of pus that has built up within the tissue of the body. Signs and symptoms of abscesses include redness, pain, warmth, and swelling. The swelling may feel fluid-filled when pressed. The area of redness often extends b ...
fluid during neutrophil
cell death
Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...
, along with other antimicrobial proteins.
Mammalian cells secrete calprotectin during the
inflammatory response
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...
. Circulating activated platelets and platelet-leukocyte aggregates are increased in acute and chronic sterile thrombo-inflammatory diseases.
Plasma
Plasma or plasm may refer to:
Science
* Plasma (physics), one of the four fundamental states of matter
* Plasma (mineral), a green translucent silica mineral
* Quark–gluon plasma, a state of matter in quantum chromodynamics
Biology
* Blood pla ...
calprotectin is elevated in persons with
metabolic syndrome
Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).
Metabolic syndrome ...
, a disease characterized by chronic inflammation.
Calprotectin is secreted in the mouth during inflammation of the
gingiva
The gums or gingiva (plural: ''gingivae'') consist of the mucosal tissue that lies over the mandible and maxilla inside the mouth. Gum health and disease can have an effect on general health.
Structure
The gums are part of the soft tissue lini ...
and during oral
candidiasis
Candidiasis is a fungal infection due to any type of '' Candida'' (a type of yeast). When it affects the mouth, in some countries it is commonly called thrush. Signs and symptoms include white patches on the tongue or other areas of the mouth ...
infection.
People who have
mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
in the calprotectin gene appear susceptible to serious gum infections.
Manganese sequestration by calprotectin is likely important during lung inflammation.
The exact mechanism by which S100A8 and S100A9 is secreted by mammalian cells during inflammation remains unknown.
In lung autopsies from patients with inflammation caused by
COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
, heterodimeric S100A8/A9 is mainly detected in neutrophils and deposited on vessel walls.
Platelet glycoprotein Ib alpha (
GP1BA
Platelet glycoprotein Ib alpha chain also known as glycoprotein Ib (platelet), alpha polypeptide or CD42b (Cluster of Differentiation 42b), is a protein that in humans is encoded by the ''GP1BA'' gene.
Function
Glycoprotein Ib (GP Ib) is a pla ...
;GPIbα) is the receptor for S100A8/A9 on platelets.
In vitro, platelets adhere to and partially spread on S100A8/A9, leading to the formation of distinct populations of P-selectin
+ and phosphatidylserine
+ platelets. The prothrombotic pathway initiated by interaction of S100A8/A9 with GPIbα induces the formation of procoagulant platelets and fibrin (
CD36
CD36 (cluster of differentiation 36), also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV) is a protein that in humans is enco ...
has a supporting role).
Antimicrobial properties
Transition metals are essential to the survival of all organisms.
Mammals strictly limit metal availability as a part of the innate immune system, and this helps prevent infection by microbes and fungi.
Calprotectin was first described in the 1980s as a mammalian antimicrobial protein that acts through the
sequestration of zinc.
It is now known that calprotectin also has
antibacterial
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
and
antifungal
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as crypto ...
properties that arise from its ability to sequester manganese and iron.
Calprotectin is the only known antimicrobial agent that acts through manganese sequestration.
Faecal calprotectin
Calprotectin becomes available in the
intestinal lumen
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...
via
leukocyte
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
shedding,
active secretion,
cell disturbance, and cell death.
This results in elevated
faecal calprotectin
Faecal calprotectin (American and British English spelling differences#ae and oe, or fecal calprotectin) is a stool test, biochemical measurement of the protein calprotectin in the human feces, stool. Elevated faecal calprotectin indicates the mig ...
levels, which can be detected in the
stool.
Elevated faecal calprotectin levels therefore indicate migration of neutrophils into the intestinal
mucosa
A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
, which occurs during intestinal inflammation.
As people with active
inflammatory bowel diseases
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine and large intestine, as well ...
(IBD) such as
ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and a ...
or
Crohn disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...
have as much as a 10-fold increase in faecal calprotectin levels,
the measurement of faecal calprotectin can serve as a
biochemical test for these diseases.
Although a relatively new test, faecal calprotectin is regularly used as an indicator for IBD during treatment and as a diagnostic marker.
Faecal calprotectin tests can also function in distinguishing patients with
irritable bowel syndrome
Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms may ...
from those with IBD.
Calprotectin is useful as a marker, as it is resistant to
enzymatic
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
degradation, and can be easily measured in
faeces
Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a relati ...
.
Although faecal calprotectin correlates significantly with disease activity in people with confirmed IBD,
elevated faecal calprotectin can be a
false-positive
A false positive is an error in binary classification in which a test result incorrectly indicates the presence of a condition (such as a disease when the disease is not present), while a false negative is the opposite error, where the test result ...
indicator of IBD under some conditions. Importantly, intake of
proton pump inhibitor
Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump.
They are the most potent inhibitors ...
is associated with significantly elevated calprotectin values.
Furthermore, positive faecal calprotectin does not help in localizing IBD, or in distinguishing ulcerative colitis from Crohn's disease.
Faecal calprotectin can also indicate other gastrointestinal conditions such as colorectal cancer, gastroenteritis, and food intolerance.
Calprotectin levels vary depending on age, comorbidity, and may vary day-to-day within individuals.
Faecal calprotectin could be used as a preliminary screen in otherwise functional patients suspected of having IBD, or as a means of following mucosal healing.
The potential for using faecal calprotectin in this way is debated, however, and cut-off levels have not been agreed upon.
See also
*
Zinc in biology
*
Manganese in biology
*
Nutritional role of calcium
*
Bioinorganic Chemistry
Bioinorganic chemistry is a field that examines the role of metals in biology. Bioinorganic chemistry includes the study of both natural phenomena such as the behavior of metalloproteins as well as artificially introduced metals, including those t ...
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Protein complexes
S100 proteins