Macroglobulin

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IgM, pictured, is an example of a macroglobulin. Another example is alpha-2 macroglobulin. IgM scheme.svg
IgM, pictured, is an example of a macroglobulin. Another example is alpha-2 macroglobulin.

Macroglobulins are large globular proteins and are found in the blood and other body fluids. Various physiological processes, including immunity, coagulation, and chemical transport, rely on these proteins. A macroglobulin is a plasma globulin of high molecular weight. [1] Elevated levels of macroglobulins (macroglobulinemia) may cause manifestations of excess blood viscosity (as is the case for IgM antibodies in Waldenström macroglobulinemia) and/or precipitate within blood vessels when temperature drops (as in cryoglobulinaemia). Other macroglobulins include α2-macroglobulin, which is elevated in nephrotic syndrome, diabetes, severe burns, and other conditions, while a deficiency is associated with chronic obstructive pulmonary disease.

Contents

Structure

Macroglobulins range in molecular weight from 400,000 to 720,000 Daltons. They are made up of four distinguishing subunits [2] that each possess multiple domains. Disulfide bonds and non-covalent interactions allow the subunits to stay together. One zinc atom also occupies a position in each subunit, aiding to maintain the stability of tetramers. The macroglobulin tetramers can be irreversibly dissociated into dimers by metalscontraions as well as chaotropic substances like urea and guanidine hydrochloride. Despite being similar in structure to immunoglobulins (Ig), macroglobulins have a distinct Y-shaped conformation. A sequence of 16 amino acids at the C-terminus of each subunit provides a highly polar, hydrophobic, binding site that can bind any sterically accessible molecule.

Types of Macroglobulins but With an Emphasis on alpha-2 Macroglobulin

There’s four primary main types of macroglobulins, alpha-2 macroglobulin, beta-2 macroglobulin, pregnancy-associated plasma protein-A, and complement component C4-binding protein. Alpha-2 macroglobulin is studied the most. Alpha-2 macroglobulin is a notable plasma component with a molecular mass of 820 kDa, about 300 mg/100 ml, and around 10% carbohydrate in 31 glycans. Alpha-2 macroglobulin is a tetrameric protein which means, in essence, that it is predominantly made up of four identical subunits. Alpha-2 macroglobulin's identical subunits contain 1451 amino acid residues. [3] Each subunit has several domains, of which include a bait region that can engage with different surface receptors on cells and proteases, and a receptor-binding domain. Alpha-2 macroglobulin is important in regulating protease activity in the blood. There are no known full oligosaccharide structures. Alpha-2 macroglobulin is also the largest non-immunoglobulin molecule found among the several highly abundant proteins in peripheral blood circulation. [4]

. Endothelial cells and hepatocytes interact with each other in order to produce alpha-2 macroglobulin where it resides mostly in the liver. A wide range of serine, threonine, pro-inflammatory cytokines, and metalloproteases can be inhibited by alpha-2 macroglobulin. Additionally, it can activate a number of genes necessary for cell oncogenesis, atherosclerosis, and proliferation/hypertrophy.

alpha-2 Macroglobulin's Function

In the plasma and tissues of vertebrates, alpha 2-macroglobulin and similar proteins act as humoral defensive barriers against pathogens by binding onto host or foreign peptides and particles. Human alpha-2 macroglobulin can facilitate the reverse or irreversible capture of proteins with a multitude of biological activities via reactive sites generated by activated molecules, such as transglutaminase cross-linking sites, thioester, and high-affinity zinc sites. The fact that alpha-2 macroglobulin interacts with and engulfs nearly any proteinase it comes across, whether it is native or foreign, suggests that it has a been designated a special role as a "panproteinase inhibitor." De novo binding sites are then created by the activation of alpha-2 macroglobulin and are used to facilitate and organize the establishment of complexes with cytokines and other peptides. The direct physical interrelation of cytokines with activated alpha-2 macroglobulin in cell cultures suggested that it has a function as a biological response modulator.

Evolutionary History

The earliest known members of the macroglobulin family of proteins initially emerged roughly 500–700 million years ago. Presently, members of the macroglobulin family have been identified in crustaceans, molluscs, fish, amphibians, reptiles, ticks, insects, birds, and mammals. The blood of some species show that multiple members of the macroglobulin family have different molecular weights and partially redundant functions. Today, macroglobulin can be found as monomers, dimers, or tetramers in a large range of different species. Each and every protein component can be characterized by having a "trap" which is composed of a cyclic thioether on the bottom and a sizable hydrophobic region. Each representation can administer a variety of regulatory tasks since complexes can be built with various regulatory chemicals via covalent or hydrophobic interactions.The macroglobulin family of proteins can be referred to as the primary regulating macromolecules of organism fluid media because of their lengthy evolutionary history, broad distribution, inherent preservation, and variety of regulatory roles. Mammals have the greatest growth of the alpha-2 macroglobulin family. There is a study of rats that is particularly interesting because the alpha-2 macroglobulin that predominates in rats differs from human alpha-2 macroglobulin by having an extra sulfide bond within the subunit; as a result, it is actually made up of eight subunits. Two macroglobulins with identical qualities first occur in fish whose alpha-2 macroglobulin are represented by tetramer forms, one of which is exclusively found in blood and the other only in eggs. This can be explained by the divergence of the gene's ancestor and the direct linkage of the egg alpha-2 macroglobulin gene to the reproductive process, which necessitates the mobilization of proliferative components. It should be emphasized that complement system proteins first appeared in fish and are structurally and functionally identical to related human proteins. [5]

Waldenström Macroglobulinemia

Waldenström macroglobulinemia is a slow-silent disease that typically develops when a person is around 65 or older, is male, has a family history of lymphoma, and is caucasian. [6] The condition is called Waldenström macroglobulinemia because the abnormal cells generate excessive levels of IgM which is the biggest immunoglobulin protein, and is also one of the causes of the condition. Interestingly, some affected people will exhibit these elevated IgM and lymphoplasmacytic cell levels but display no symptoms of the disease; in these people, the illness is typically discovered by fluke after a blood test that was performed for an entirely different medical reason. Smoldering Waldenström macroglobulinemia is the diagnosis for these people who present asymptomatic to it. Before a person with the illness exhibits observable signs and symptoms, it can take many years. Waldenström macroglobulinemia is an uncommon cancer of the blood cells that is distinguished by the proliferation of abnormal white blood cells within the bone marrow. These aberrant cells resemble both B cells, which are white blood cells, also known as lymphocytes, and plasma cells, which are B cells that went through a secondary type of development. The term "lymphoplasmacytic cells" refers to these irregular cells that display both lymphocyte and plasma-like features. Waldenström macroglobulinemia is categorized as a lymphoplasmacytic lymphoma as a result of these cells. [7]

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<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellular bacteria, protozoa, helminths, and fungi which could cause serious problems to the health of the host organism if not cleared from the body.

<span class="mw-page-title-main">B cell</span> Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. Additionally, B cells present antigens and secrete cytokines. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the 'B' stands for bursa and not bone marrow as commonly believed.

<span class="mw-page-title-main">Mast cell</span> Cell found in connective tissue

A mast cell 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 part of the immune and neuroimmune systems. Mast cells were discovered by Paul Ehrlich in 1877. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing, angiogenesis, immune tolerance, defense against pathogens, and vascular permeability in brain tumors.

<span class="mw-page-title-main">Serum protein electrophoresis</span> Laboratory test

Serum protein electrophoresis is a laboratory test that examines specific proteins in the blood called globulins. The most common indications for a serum protein electrophoresis test are to diagnose or monitor multiple myeloma, a monoclonal gammopathy of uncertain significance (MGUS), or further investigate a discrepancy between a low albumin and a relatively high total protein. Unexplained bone pain, anemia, proteinuria, chronic kidney disease, and hypercalcemia are also signs of multiple myeloma, and indications for SPE. Blood must first be collected, usually into an airtight vial or syringe. Electrophoresis is a laboratory technique in which the blood serum is applied to either an acetate membrane soaked in a liquid buffer, or to a buffered agarose gel matrix, or into liquid in a capillary tube, and exposed to an electric current to separate the serum protein components into five major fractions by size and electrical charge: serum albumin, alpha-1 globulins, alpha-2 globulins, beta 1 and 2 globulins, and gamma globulins.

Humoral immunity is the aspect of immunity that is mediated by macromolecules - including secreted antibodies, complement proteins, and certain antimicrobial peptides - located in extracellular fluids. Humoral immunity is named so because it involves substances found in the humors, or body fluids. It contrasts with cell-mediated immunity. Humoral immunity is also referred to as antibody-mediated immunity.

<span class="mw-page-title-main">Index of biochemistry articles</span>

Biochemistry is the study of the chemical processes in living organisms. It deals with the structure and function of cellular components such as proteins, carbohydrates, lipids, nucleic acids and other biomolecules.

The globulins are a family of globular proteins that have higher molecular weights than albumins and are insoluble in pure water but dissolve in dilute salt solutions. Some globulins are produced in the liver, while others are made by the immune system. Globulins, albumins, and fibrinogen are the major blood proteins. The normal concentration of globulins in human blood is about 2.6-3.5 g/dL.

alpha-2-Macroglobulin Large plasma protein found in the blood

α2-Macroglobulin (α2M) or alpha-2-macroglobulin is a large plasma protein found in the blood. It is mainly produced by the liver, and also locally synthesized by macrophages, fibroblasts, and adrenocortical cells. In humans it is encoded by the A2M gene.

<span class="mw-page-title-main">Cryoglobulinemia</span> Medical condition

Cryoglobulinemia is a medical condition in which the blood contains large amounts of pathological cold sensitive antibodies called cryoglobulins – proteins that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells.

Waldenström macroglobulinemia is a type of cancer affecting two types of B cells: lymphoplasmacytoid cells and plasma cells. Both cell types are white blood cells. It is characterized by having high levels of a circulating antibody, immunoglobulin M (IgM), which is made and secreted by the cells involved in the disease. Waldenström macroglobulinemia is an "indolent lymphoma" and a type of lymphoproliferative disease which shares clinical characteristics with the indolent non-Hodgkin lymphomas. It is commonly classified as a form of plasma cell dyscrasia, similar to other plasma cell dyscrasias that, for example, lead to multiple myeloma. Waldenström macroglobulinemia is commonly preceded by two clinically asymptomatic but progressively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenström macroglobulinemia. The Waldenström macroglobulinemia spectrum of dysplasias differs from other spectrums of plasma cell dyscrasias in that it involves not only aberrant plasma cells but also aberrant lymphoplasmacytoid cells and that it involves IgM while other plasma dyscrasias involve other antibody isoforms.


Interleukin 5 (IL5) is an interleukin produced by type-2 T helper cells and mast cells.

<span class="mw-page-title-main">Monoclonal gammopathy</span> Excess myeloma protein or monoclonal gamma globulin in the blood

Monoclonal gammopathy, also known as paraproteinemia, is the presence of excessive amounts of myeloma protein or monoclonal gamma globulin in the blood. It is usually due to an underlying immunoproliferative disorder or hematologic neoplasms, especially multiple myeloma. It is sometimes considered equivalent to plasma cell dyscrasia. The most common form of the disease is monoclonal gammopathy of undetermined significance.

Macroglobulinemia is the presence of increased levels of macroglobulins in the circulating blood. It is a plasma cell dyscrasia, resembling leukemia, with cells of lymphocytic, plasmacytic, or intermediate morphology, which secrete a monoclonal immunoglobulin M component. There is diffuse infiltration by the malignant cells of the bone marrow and also, in many cases, of the spleen, liver, or lymph nodes. The circulating macroglobulin can produce symptoms of hyperviscosity syndrome: weakness, fatigue, bleeding disorders, and visual disturbances. Peak incidence of macroglobulinemia is in the sixth and seventh decades of life.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

<span class="mw-page-title-main">B-cell receptor</span> Transmembrane protein on the surface of a B cell

The B-cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B-cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor protein, and is typically located on the outer surface of these lymphocyte cells. Through biochemical signaling and by physically acquiring antigens from the immune synapses, the BCR controls the activation of the B cell. B cells are able to gather and grab antigens by engaging biochemical modules for receptor clustering, cell spreading, generation of pulling forces, and receptor transport, which eventually culminates in endocytosis and antigen presentation. B cells' mechanical activity adheres to a pattern of negative and positive feedbacks that regulate the quantity of removed antigen by manipulating the dynamic of BCR–antigen bonds directly. Particularly, grouping and spreading increase the relation of antigen with BCR, thereby proving sensitivity and amplification. On the other hand, pulling forces delinks the antigen from the BCR, thus testing the quality of antigen binding.

<span class="mw-page-title-main">Alveolar macrophage</span>

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The following outline is provided as an overview of and topical guide to immunology:

In hematology, plasma cell dyscrasias are a spectrum of progressively more severe monoclonal gammopathies in which a clone or multiple clones of pre-malignant or malignant plasma cells over-produce and secrete into the blood stream a myeloma protein, i.e. an abnormal monoclonal antibody or portion thereof. The exception to this rule is the disorder termed non-secretory multiple myeloma; this disorder is a form of plasma cell dyscrasia in which no myeloma protein is detected in serum or urine of individuals who have clear evidence of an increase in clonal bone marrow plasma cells and/or evidence of clonal plasma cell-mediated tissue injury. Here, a clone of plasma cells refers to group of plasma cells that are abnormal in that they have an identical genetic identity and therefore are descendants of a single genetically distinct ancestor cell.

Lysine carboxypeptidase is an enzyme. This enzyme catalyses the following chemical reaction:

References

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  2. "Macroglobulin - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2023-05-02.
  3. "Protein structure", Wikipedia, 2023-01-26, retrieved 2023-05-02
  4. Wilson, William W.; Haiges, Ralf; Christe, Karl (2023-04-12). "Contents Lists Available at Sciencedirect". Rochester, NY. SSRN   4417034.{{cite journal}}: Cite journal requires |journal= (help)
  5. Zorin, N. A.; Zorina, V. N.; Zorina, R. M. (2006-01-01). "Evolution of proteins of macroglobulin family". Journal of Evolutionary Biochemistry and Physiology. 42 (1): 112–116. doi:10.1134/S0022093006010157. ISSN   1608-3202.
  6. "Waldenstrom macroglobulinemia - Symptoms and causes". Mayo Clinic. Retrieved 2023-05-02.
  7. "Waldenström macroglobulinemia: MedlinePlus Genetics". medlineplus.gov. Retrieved 2023-05-02.