Protein M

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IgG-blocking protein M
Identifiers
SymbolM_MG281
InterPro IPR030943
Uncharacterized protein MG281
Identifiers
Organism Mycoplasma genitalium ATCC 33530
SymbolMG281
UniProt P47523
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Structures Swiss-model
Domains InterPro

Protein M (locus MG281) is an immunoglobulin-binding protein originally found on the cell surface of the human pathogenic bacterium Mycoplasma genitalium . It is presumably a universal antibody-binding protein, as it is known to be reactive against all antibody types tested so far. It is capable of preventing the antigen-antibody interaction due to its high binding affinity to any antibody. The Scripps Research Institute announced its discovery in 2014. [1] It was detected from the bacterium while investigating its role in patients with a cancer, multiple myeloma. [2] [3]

Contents

Homologous proteins are found in other Mycoplasma bacteria. [2] Mycoplasma pneumoniae , another human pathogen, has a homolog termed IbpM (locus MPN400). [4]

Discovery

Mycoplasma genitalium was discovered in 1980 from two male patients with non-gonococcal urethritis at St Mary's Hospital, Paddington, London. [5] After two years, in 1983, it was identified as a new species. [6] After several years of intense research, it was found to be the cause of sexually transmitted diseases, such as urethritis (inflammation of the urinary tract) both in men and women, and also cervicitis (inflammation of cervix) and pelvic inflammation in women. [7] [8] However, the molecular nature of its pathogenicity remained unknown for three decades.[ citation needed ]

On 6 February 2014, The Scripps Research Institute announced the discovery of a novel protein, which they named Protein M, from the M. genitalium cell membrane. [1] Scientists identified the protein during investigations on the origin of multiple myeloma, a type of B-cell carcinoma. To understand the long-term M. genitalium infection, Rajesh Grover, a senior staff scientist in the Lerner laboratory, tested antibodies from the blood samples of patients with multiple myeloma against different Mycoplasma species. He found that M. genitalium was particularly responsive to all types of antibodies he tested from 20 patients. [9] The antibody reactivity was found to be due to an undiscovered protein that is chemically responsive to all types of human and non-human antibodies available. [10] When they isolated and analysed the protein, they discovered that it was unique both in structure and biological functions. Its structure has no resemblance to any known protein listed in the Protein Data Bank. [2]

Structure and properties

Protein M is about 50 kDa in size, and composed of 556 amino acids. Contrary to the initial hypothesis that the antibody reactions could be an immune response to mass infection with the bacterium, they found that Protein M evolved simply to bind to any antibody it encounters, with specifically high affinity. By this property the bacterium can effectively evade the immune system of the host. This makes the protein an ideal target for developing new drugs. [11] [12] Rajesh Grover estimated that the protein can bind to an average of 100,000,000 different kinds of antibodies circulating in human blood. [13]

Unlike functionally similar proteins such as Protein A, Protein G, and Protein L, which all contain small, multiple immunoglobulin domains, Protein M has a large domain of 360 amino acid residues that binds primarily to the variable light chain of the immunoglobulin, as well as a binding site called LRR-like motif. In addition, Protein M has a C-terminal domain with 115 amino acid residues that probably protrudes over the antibody binding site. It binds to an antibody at either κ or λ light chains using hydrogen bonds and salt bridges, from backbone atoms and conserved side chains, and some conserved van der Waals interactions with other nonconserved interactions. [2]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. The term antigen originally referred to a substance that is an antibody generator. Antigens can be proteins, peptides, polysaccharides, lipids, or nucleic acids.

<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.

<i>Mycoplasma genitalium</i> Species of bacterium

Mycoplasma genitalium is a sexually transmitted, small and pathogenic bacterium that lives on the mucous epithelial cells of the urinary and genital tracts in humans. Medical reports published in 2007 and 2015 state that Mgen is becoming increasingly common. Resistance to multiple antibiotics is becoming prevalent, including to azithromycin, which until recently was the most reliable treatment. The bacteria was first isolated from the urogenital tract of humans in 1981, and was eventually identified as a new species of Mycoplasma in 1983. It can cause negative health effects in men and women. It also increases the risk factor for HIV spread with higher occurrences in those previously treated with the azithromycin antibiotics.

<i>Neisseria gonorrhoeae</i> Species of bacterium

Neisseria gonorrhoeae, also known as gonococcus (singular), or gonococci (plural), is a species of Gram-negative diplococci bacteria isolated by Albert Neisser in 1879. It causes the sexually transmitted genitourinary infection gonorrhea as well as other forms of gonococcal disease including disseminated gonococcemia, septic arthritis, and gonococcal ophthalmia neonatorum.

<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.

Nongonococcal urethritis (NGU) is an inflammation of the urethra that is not caused by gonorrheal infection.

<span class="mw-page-title-main">Monoclonal antibody</span> Antibodies from clones of the same blood cell

A monoclonal antibody is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.

Immunoglobulin G is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG antibody has two paratopes.

<span class="mw-page-title-main">Immunoglobulin M</span> One of several isotypes of antibody

Immunoglobulin M (IgM) is one of several isotypes of antibody that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antigen. In humans and other mammals that have been studied, plasmablasts residing in the spleen are the main source for specific IgM production.

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 part of an antibody that binds to the epitope is called a paratope. Although epitopes are usually non-self proteins, sequences derived from the host that can be recognized are also epitopes.

Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted:

<span class="mw-page-title-main">Antibody-dependent cellular cytotoxicity</span> Cell-mediated killing of other cells mediated by antibodies

Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.

<span class="mw-page-title-main">Protein A</span>

Protein A is a 42 kDa surface protein originally found in the cell wall of the bacteria Staphylococcus aureus. It is encoded by the spa gene and its regulation is controlled by DNA topology, cellular osmolarity, and a two-component system called ArlS-ArlR. It has found use in biochemical research because of its ability to bind immunoglobulins. It is composed of five homologous Ig-binding domains that fold into a three-helix bundle. Each domain is able to bind proteins from many mammalian species, most notably IgGs. It binds the heavy chain within the Fc region of most immunoglobulins and also within the Fab region in the case of the human VH3 family. Through these interactions in serum, where IgG molecules are bound in the wrong orientation, the bacteria disrupts opsonization and phagocytosis.

<span class="mw-page-title-main">Complement component 1q</span> Protein complex

The complement component 1q is a protein complex involved in the complement system, which is part of the innate immune system. C1q together with C1r and C1s form the C1 complex.

<span class="mw-page-title-main">Immunoglobulin light chain</span> Small antibody polypeptide subunit (immunoglobin)

The immunoglobulin light chain is the small polypeptide subunit of an antibody (immunoglobulin).

<span class="mw-page-title-main">Protein L</span>

Protein L was first isolated from the surface of bacterial species Peptostreptococcus magnus and was found to bind immunoglobulins through L chain interaction, from which the name was suggested. It consists of 719 amino acid residues. The molecular weight of Protein L purified from the cell walls of Peptostreptoccus magnus was first estimated as 95kD by SDS-PAGE in the presence of reducing agent 2-mercaptoethanol, while the molecular weight was determined to 76kD by gel chromotography in the presence of 6 M guanidine HCl. Protein L does not contain any interchain disulfide loops, nor does it consist of disulfide-linked subunits. It is an acidic molecule with a pI of 4.0. Unlike Protein A and Protein G, which bind to the Fc region of immunoglobulins (antibodies), Protein L binds antibodies through light chain interactions. Since no part of the heavy chain is involved in the binding interaction, Protein L binds a wider range of antibody classes than Protein A or G. Protein L binds to representatives of all antibody classes, including IgG, IgM, IgA, IgE and IgD. Single chain variable fragments (scFv) and Fab fragments also bind to Protein L.

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Passive antibody therapy, also called serum therapy, is a subtype of passive immunotherapy that administers antibodies to target and kill pathogens or cancer cells. It is designed to draw support from foreign antibodies that are donated from a person, extracted from animals, or made in the laboratory to elicit an immune response instead of relying on the innate immune system to fight disease. It has a long history from the 18th century for treating infectious diseases and is now a common cancer treatment. The mechanism of actions include: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).

References

  1. 1 2 "The Ultimate Decoy: Scripps Research Institute Scientists Find Protein that Helps Bacteria Misdirect Immune System". The Scripps Research Institute (TSRI). Retrieved 9 August 2014.
  2. 1 2 3 4 Grover RK, Zhu X, Nieusma T, Jones T, Boreo I, MacLeod AS, et al. (February 2014). "A structurally distinct human mycoplasma protein that generically blocks antigen-antibody union". Science. 343 (6171): 656–661. Bibcode:2014Sci...343..656G. doi:10.1126/science.1246135. PMC   3987992 . PMID   24503852.
  3. ↑ Hofer U (April 2014). "Bacterial physiology: mycoplasmal protein binds antibodies". Nature Reviews. Microbiology. 12 (4): 234–235. doi:10.1038/nrmicro3233. PMID   24531616. S2CID   8739794.
  4. ↑ Blötz C, Singh N, Dumke R, Stülke J (2020). "Characterization of an Immunoglobulin Binding Protein (IbpM) From Mycoplasma pneumoniae". Frontiers in Microbiology. 11: 685. doi: 10.3389/fmicb.2020.00685 . PMC   7176901 . PMID   32373096.
  5. ↑ Tully JG, Taylor-Robinson D, Cole RM, Rose DL (June 1981). "A newly discovered mycoplasma in the human urogenital tract". Lancet. 1 (8233): 1288–1291. doi:10.1016/S0140-6736(81)92461-2. PMID   6112607. S2CID   31023747.
  6. ↑ Tully JG, Taylor-robinson D, Rose DL, Cole RM, Bove JM (1983). "Mycoplasma genitalium, a New Species from the Human Urogenital Tract". International Journal of Systematic Bacteriology. 33 (2): 387–396. doi: 10.1099/00207713-33-2-387 .
  7. ↑ Taylor-Robinson D, Horner PJ (August 2001). "The role of Mycoplasma genitalium in non-gonococcal urethritis". Sexually Transmitted Infections. 77 (4): 229–231. doi:10.1136/sti.77.4.229. PMC   1744340 . PMID   11463919.
  8. ↑ Daley GM, Russell DB, Tabrizi SN, McBride J (June 2014). "Mycoplasma genitalium: a review". International Journal of STD & AIDS. 25 (7): 475–487. doi:10.1177/0956462413515196. PMID   24517928. S2CID   206582691.
  9. ↑ Voelker R (6 February 2014). "Newly Discovered Protein Helps Mycoplasma Evade Immune Response". newsatJAMA. Retrieved 9 August 2014.
  10. ↑ Mayer K (6 February 2014). "Protein Sticks to Any Antibody, Gums Up Immune Response". GEN. Genetic Engineering & Biotechnology News. Retrieved 9 August 2014.
  11. ↑ "The ultimate decoy: Protein helps bacteria misdirect immune system". ScienceDaily. 6 February 2014. Retrieved 9 August 2014.
  12. ↑ LabMedica International staff writers (20 February 2014). "A Unique Mycoplasma Protein Generically Binds All Types of Antibodies and Blocks Antigen Binding". biotechdaily. Globetech Media. Retrieved 9 August 2014.
  13. ↑ Cashin-Garbutt A (26 February 2014). "Protein M: an interview with Rajesh Grover, PhD, senior staff scientist, Lerner laboratory, TSRI". News-Medical.Net. Retrieved 9 August 2014.
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