S100 proteins are a family of low molecular weight tissue-specific calcium-binding proteins with a modulatory effect that are involved in many physiological processes in the body. The name characterizes the ability of compounds of this group to completely dissolve in a 100% ammonium sulfate solution at neutral pH values.
Currently, 25 representatives of this family are known, which are characteristic of different tissues. This feature suggests that brain-specific s100 proteins are proteins present in brain cells and involved in neurophysiological processes.
Discovery history
The first s100 protein was isolated in 1965 from bovine brains by scientists Moore and Gregor. Subsequently, proteins of this family were found in mammals, birds, reptiles, and humans. Initially, it was thought that s100 is present only in the nervous tissue, but with the development of immunological methods, proteins of this group began to be found in other organs.
General characteristics and topography
Proteins of the s100 family are present only in vertebrates and humans. Of the 25 proteins in this group, 15 are brain-specific, most of which are produced by astroglial cells in the CNS, but some are also present in neurons.
It has been established that 90% of the entire s100 fraction in the body is dissolved in the cytoplasm of cells, 0.5% is localized in the nucleus and 5-7% is associated with membranes. A small portion of the protein is found in the extracellular space, including blood and cerebrospinal fluid.
Protein of the s100 group is present in many organs (skin, liver, heart, spleen, etc.), but in the brain it is a hundred thousand times more. The highest concentration is observed in the cerebellum. The s100 protein is also actively produced in melanocytes (skin tumor cells). This has led to the use of this compound as a tissue marker of ectodermal origin.
Chemically, s100 proteins are dimers with a molecular weight of 10-12 d altons. These proteins are acidic because they contain a large amount (up to 30%) of glutamic and aspartic amino acid residues. The composition of s100 molecules does not include phosphates, carbohydrates and lipids. These proteins can withstand temperatures up to 60 degrees.
Structure and spatial conformation
The structure of all members of the s100 family are globular proteins. The composition of one dimeric molecule includes 2 polypeptides (alpha and beta), connected to each other by non-covalent bonds.
Most members of the family are homodimers formed by two identical subunits, but there are also heterodimers. Each polypeptide within the s100 molecule has a calcium-binding motif called the EF hand. It is built according to the spiral-loop-spiral type.
The s100 protein contains 4 α-helical segments, a central hinge region of variable length, and two terminal variable domains (N and C).
Features of action
S100 proteins themselves do not have enzymatic activity. Their functioning is based on the binding of calcium ions, which are involved in many intercellular and intracellular processes, including signaling. The addition of Ca2+ to the s100 molecule leads to its spatial rearrangement and the opening of the target protein-binding center, through which interaction with other proteins is carried out.
Thus, s100 do not belong to proteins whose main task is to regulate the concentration of Ca2+. Proteins of this group are signal-converting calcium-dependent biologically active modulators that affect intracellular and extracellular processes through binding to target proteins. Neurotransmitters can also act as the latter, which is the reason for the influence of s100 on the transmission of nerve impulses.
Currently, it has been revealed that zinc and/or copper ions act as regulators for some s100 instead of Ca2+. The addition of the latter can both directly affect the activity of the protein and change its affinity for calcium.
Functions
A complete picture of the biological role of brain-specific s100 proteins in the body does not yet exist. Nevertheless, the participation of proteins of this group in the following processes was revealed:
- regulation of metabolic reactions of nervous tissue;
- DNA replication;
- expression of genetic information;
- glial cell proliferation;
- Protection against oxidative (oxygen-related) cell damage;
- differentiation of immature neurons;
- death of neurons through apoptosis;
- cytoskeleton dynamics;
- phosphorylation and secretion;
- transmission of a nerve impulse;
- regulation of the cell cycle.
Depending on the species and localization, brain-specific s100 proteins can have both intracellular and extracellular effects. The effect of some proteins is concentration dependent. Thus, the well-known protein s100B at normal levels exhibits neurotrophic activity, and at elevated levels it exhibits neurotoxic activity.
Extracellular brain-specific s100 proteins may be involved in inflammatory responses, regulate glial and neuronal differentiation, and trigger apoptosis (programmed cell death). The importance of s100 was proven in an in vitro experiment in which neurons did not survive without the presence ofthis protein.
Diagnostic value s100
The diagnostic value of s100 is based on the relationship of its concentration in blood serum (or cerebrospinal fluid) with CNS pathologies and oncological diseases. It has been established that when glial cells are damaged, this protein enters the extracellular space, from where it enters the cerebrospinal fluid and then into the blood. Thus, on the basis of an increase in the concentration of s100 in the serum, a conclusion can be drawn about a number of brain pathologies. The relationship between the content of this protein in the blood and diseases of the central nervous system has been experimentally confirmed.
To increase the concentration of s100 in extracellular fluids lead not only because of the destruction of cellular barriers synthesizing this protein cells. The first response to many brain pathologies is the so-called glial response, part of which is an increase in the intensity of s100 secretion by astrocytes. An increase in the content of this protein in the blood may also indicate a violation of the blood-brain barrier.
Monitoring the level of s100 allows you to assess the degree of brain damage, which is of great importance in medical prognosis. The diagnostic relationship between the amount of this protein and neuropathology resembles the correlation of the concentration of c-reactive protein with systemic inflammation.
Use as tumor marker
The s100 protein began to be used as a tumor marker in the early 1980s. Currently, this method is effective for early detection of cancer, recurrence or metastasis. Most often s100 is used indiagnosing melanoma or neuroblastoma.
It is necessary to distinguish between when this protein is analyzed to determine CNS pathologies or other diseases, and when it is used to detect cancer. If the focus is on the oncomarker, the decoding of the s100 protein should also take into account other possible reasons for the increase in the concentration of the test substance in the blood. When interpreting the results, be sure to pay attention to the method of analysis, since the boundaries of the reference interval (normal indicators) depend on it.
The main disadvantage of the s100 marker is its low selectivity, since an increase in the concentration of this protein in the blood and CSF can be associated with many pathologies, not necessarily of a cancerous nature. Therefore, the s100 protein cannot be given a decisive diagnostic value. Nevertheless, this protein has proven itself as a companion cancer marker.
Presence level in blood serum
Normally, s100 protein should be present in serum in an amount of less than 0.105 µg/l. This value corresponds to the upper limit of concentration in a he althy person. Exceeding the permissible level (DL) s100 may indicate:
- CP;
- brain injury;
- development of malignant melanoma (or its recurrence);
- pregnancy;
- neuroblastoma;
- dermatomyositis;
- covering large areas of burns.
Protein levels can also increase with stress or prolonged exposurebody in the ultraviolet zone. The concentration in the blood is determined by the appropriate analysis.
Detection in the body
There are several ways to detect the presence of s100 in serum, including:
- immunoradiometric assay (IRMA);
- mass spectroscopy;
- western blot;
- ELISA (enzyme immunoassay);
- electrochemiluminescence;
- quantitative PCR.
All of these analytical methods are highly sensitive and allow very accurate determination of the quantitative content of s100. Since this protein has a short half-life (30 minutes), high serum concentrations are only possible with a constant supply from diseased tissues.
In clinical diagnostics, an automated electrochemiluminescent immunoassay for the s100 protein is most often used. The study combines the use of antibodies to a detectable protein with light marking. The device determines the concentration s100 by the intensity of chemiluminescent radiation.
Antibodies to protein s100
In medicine, antibodies to the s100 protein have 2 areas of practical application:
- diagnostic - used in immunological methods to detect the concentration of this protein in serum or CSF (in this case, s100 is an antigen);
- therapeutic - the introduction of antibodies into the body is used in the treatment of certain diseases.
Antibodies exert their effect through modulatingeffects on s100 proteins. A well-known drug on this basis is Tenoten. Antibodies to s100 have a beneficial effect on the nervous system, improve impulse transmission. In addition, such drugs are able to stop the symptomatic manifestations of disorders of the autonomic function in the digestive system.
