Invasin

Last updated
inverse autotransporter invasin
Identifiers
Organism Yersinia enterocolitica
Symbolinv
Entrez 77327691
PDB 1CWV
RefSeq (Prot) WP_263696614.1
UniProt P19196
Other data
Chromosome Genomic: 1.75 - 1.75 Mb
Search for
Structures Swiss-model
Domains InterPro

Invasins are a class of bacterial proteins associated with the penetration of pathogens into host cells. [1] Invasins play a role in promoting entry during the initial stage of infection. [2] [3]

Contents

In 2007, Als3 was identified as a fungal invasion allowing Candida albicans to infect host cells. [4]

Invasin is a small membrane bound protein that enables the infiltration of cultured mammalian cells by enteric bacteria. The cellular entry of invasin is facilitated through the binding of multiple β1 chain integrins. [5] The interplay between invasin and β1 integrins initiates a reconfiguration of the cytoskeleton in the target cell, culminating in the creation of a groove and the internalization of bacteria through endosomes by the cell. Invasin is expressed inYersinia enterocolitica and Yersinia pseudotuberculosis because of its outermembrane being chromosomally encoded. [6] Invasin demonstrates a significantly enhanced binding affinity to β1 integrins compared to the natural ligands of the receptor. More precisely, it forms a robust attachment to the α5β1 integrin, typically employed by fibronectin, exhibiting roughly 100 times greater strength. This heightened binding capability arises from structural disparities between the two proteins. The extracellular region of invasin adopts a rod-like configuration, with dimensions measuring approximately 180 Å by 30 Å by 30 Å. [7]

Examples

Yersinia pseudotuberculosis

Yersinia pseudotuberculosis, a Gram-negative bacterium and zoonotic pathogen, is accountable for various diseases, spanning mild diarrhea, enterocolitis, lymphatic adenitis, to enduring local inflammation. The invasin D molecule of Y. pseudotuberculosis (InvD) is classified under the invasin (InvA)-type autotransporter proteins, yet its structure and function remain undiscovered. [8] This bacterium induces a food-borne infection marked by a self-limiting mesenteric lymphadenitis that imitates symptoms of appendicitis. [9]

Yersinia enterocolitica

Yersinia enterocolitica is a gram-negative bacillus-shaped bacterium that gives rise to yersiniosis, a zoonotic disease. This infection presents as acute diarrhea, mesenteric adenitis, terminal ileitis, and pseudoappendicitis, occasionally progressing to sepsis. In certain regions, yersinia infections have surpassed shigella and salmonella species as the leading cause of bacterial gastroenteritis. While most cases occur sporadically, notable outbreaks are not uncommon. Humans typically contract yersinia through the consumption of contaminated food or blood transfusions. Y. enterocolitica has been detected in various animals, with pigs serving as the primary reservoir. The pathogen can disseminate within pig herds, contaminating pork products like neck trimmings, tongue, and tonsils, potentially spreading to other meat cuts during the slaughtering process. [10]

Structure

The extracellular region of invasin, composed of the COOH-terminal 497 residues, can be expressed as a soluble protein (Inv497). This protein binds to integrins and facilitates uptake when attached to bacteria or beads. The shortest invasin fragment capable of integrin binding consists of the COOH-terminal 192 amino acids. Notably, this fragment lacks homology with the integrin-binding domains of fibronectin, specifically the fibronectin type III repeats 9 and 10 (Fn-III 9–10). However, invasin and fibronectin share binding sites on α3β1 and α5β1 integrins, with the integrin-binding region of invasin showing no significant sequence identity with the corresponding regions of intimins. [11]

Invasin residues crucial for integrin binding are at positions 903 to 913, constituting helix 1 and the subsequent loop in D5. The disulfide bond between Cys906 and Cys982, a conserved feature in all CTLDs, is essential for integrin binding, likely due to its role in ensuring proper folding. Despite the absence of an Arg-Gly-Asp (RGD) sequence, a critical element in Fn-III 10 for interacting with integrins, invasin relies on Asp911 in Inv497 D5 for integrin binding. Similar to the aspartate in the Fn-III RGD sequence, Asp911 is situated within a loop. Another invasin region, approximately 100 amino acids from Asp911, contains additional residues implicated in integrin binding, including Asp811. This particular invasin segment bears a resemblance to the fibronectin synergy region in Fn-III 9, crucial for optimal α5β1 integrin-dependent cell spreading. Invasin Asp811, positioned in D4 between strands A" and A‴, shares the same surface as Asp911, separated by a distance of 32 Å. The distance between Fn-III 10 Asp1495 in the RGD sequence and Fn-III 9 Asp1373 in the synergy region is also 32 Å, although the side-chain orientation of Asp1373 differs from that of Asp811 in invasin. Within the Fn-III synergy region, the residue for integrin binding is Arg1379. Invasin and host proteins have integrin-binding features that are fairly similar. [11]

The transmembrane segments of outer membrane proteins with known structures exhibit a β-barrel architecture, exemplified by porins. Assuming that the membrane-associated section of invasin also forms a β-barrel, with the cell-binding region extending approximately 180 Å from the bacterial surface, it is positioned to engage host cell integrins. The parallels between invasin and fibronectin indicate the convergent evolution of shared integrin-binding characteristics. Unlike the fibronectin-binding surface, the integrin-binding region of the invasin lacks a cleft; which can result in invasin binding integrins with a larger interface. [11]

Mechanism of action

The invasin-mediated uptake into mammalian cells involves a clustering model. Multivalent invasin induces integrin clustering by simultaneously binding to multiple integrin heterodimers. This process, dependent on ligand binding and b1-integrin multimerization, leads to the association of various cell signaling molecules, triggering the involvement of additional signaling and cytoskeletal proteins. Invasin mechanism of action in bacterial cells.jpg
The invasin-mediated uptake into mammalian cells involves a clustering model. Multivalent invasin induces integrin clustering by simultaneously binding to multiple integrin heterodimers. This process, dependent on ligand binding and β1-integrin multimerization, leads to the association of various cell signaling molecules, triggering the involvement of additional signaling and cytoskeletal proteins.

Entry into M-cells occurs by utilizing a small membrane-bound protein known as invasin. This protein exhibits a strong attraction to the b1 superfamily of integrins present on the outer surface of various mammalian cells. Interestingly, these integrins do not play a role in particle ingestion; instead, they are involved in processes like adhesion to the extracellular matrix, interactions with cell surfaces, migration, and differentiation. The natural partners of these receptors include fibronectin, collagen, vitronectin, and laminin, although invasin forms a stronger bond with them. Notably, invasin selectively binds to specific members within the β1 integrins family. Invasin will bind exclusively to a subset of the b1 subfamily of integrins, specifically α3β1, α4β1, α5β1, α6β1, and αVβ1. [7]

Potential applications

The invasin protein has a particular interest in future use in oral gene discovery. Delivering genes non-virally through oral administration holds great promise for enhancing the efficacy of DNA vaccination and gene therapy applications. Unlike traditional parenteral routes, the oral approach is non-invasive, promoting increased patient compliance and simplified dosing. Furthermore, oral administration enables the production of therapeutic genes locally and systemically. In the case of DNA vaccination, it fosters the development of both mucosal and systemic immunity. [13]

Related Research Articles

<span class="mw-page-title-main">Integrin</span> Instance of a defined set in Homo sapiens with Reactome ID (R-HSA-374573)

Integrins are transmembrane receptors that help 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, organization of the intracellular cytoskeleton, and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface.

<i>Yersinia pestis</i> Species of bacteria, cause of plague

Yersinia pestis is a gram-negative, non-motile, coccobacillus bacterium without spores that is related to both Yersinia enterocolitica and Yersinia pseudotuberculosis, the pathogen from which Y. pestis evolved and responsible for the Far East scarlet-like fever. It is a facultative anaerobic organism that can infect humans via the Oriental rat flea. It causes the disease plague, which caused the Plague of Justinian and the Black Death, the deadliest pandemic in recorded history. Plague takes three main forms: pneumonic, septicemic, and bubonic. Yersinia pestis is a parasite of its host, the rat flea, which is also a parasite of rats, hence Y. pestis is a hyperparasite.

<span class="mw-page-title-main">Fibronectin</span> Protein involved in cell adhesion, cell growth, cell migration and differentiation

Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. It is approved for marketing as a topical solution in India by Central Drugs Standard Control organization in 2020 under the brand name FIBREGA for chronic wounds. Fibronectin also binds to other extracellular matrix proteins such as collagen, fibrin, and heparan sulfate proteoglycans.

<span class="mw-page-title-main">Pertactin</span> Virulence factor of Bordetella pertussis

In molecular biology, pertactin (PRN) is a highly immunogenic virulence factor of Bordetella pertussis, the bacterium that causes pertussis. Specifically, it is an outer membrane protein that promotes adhesion to tracheal epithelial cells. PRN is purified from Bordetella pertussis and is used for the vaccine production as one of the important components of acellular pertussis vaccine.

<i>Yersinia enterocolitica</i> Species of bacterium

Yersinia enterocolitica is a Gram-negative, rod-shaped bacterium, belonging to the family Yersiniaceae. It is motile at temperatures of 22–29°C (72–84°F), but becomes nonmotile at normal human body temperature. Y. enterocolitica infection causes the disease yersiniosis, which is an animal-borne disease occurring in humans, as well as in a wide array of animals such as cattle, deer, pigs, and birds. Many of these animals recover from the disease and become carriers; these are potential sources of contagion despite showing no signs of disease. The bacterium infects the host by sticking to its cells using trimeric autotransporter adhesins.

<i>Yersinia pseudotuberculosis</i> Species of bacterium

Yersinia pseudotuberculosis is a Gram-negative bacterium that causes Far East scarlet-like fever in humans, who occasionally get infected zoonotically, most often through the food-borne route. Animals are also infected by Y. pseudotuberculosis. The bacterium is urease positive.

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

Intimin is a virulence factor (adhesin) of EPEC and EHEC E. coli strains. It is an attaching and effacing (A/E) protein, which with other virulence factors is necessary and responsible for enteropathogenic and enterohaemorrhagic diarrhoea.

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<span class="mw-page-title-main">OmpA-like transmembrane domain</span>

OmpA-like transmembrane domain is an evolutionarily conserved domain of bacterial outer membrane proteins. This domain consists of an eight-stranded beta barrel. OmpA is the predominant cell surface antigen in enterobacteria found in about 100,000 copies per cell. The expression of OmpA is tightly regulated by a variety of mechanisms. One mechanism by which OmpA expression is regulated in Vibrio species is by an antisense non-coding RNA called VrrA.

<span class="mw-page-title-main">Virulence-related outer membrane protein family</span>

Virulence-related outer membrane proteins, or outer surface proteins (Osp) in some contexts, are expressed in the outer membrane of gram-negative bacteria and are essential to bacterial survival within macrophages and for eukaryotic cell invasion.

<span class="mw-page-title-main">Integrin alpha 9</span> Protein-coding gene in the species Homo sapiens

Integrin alpha-9 is a protein that in humans is encoded by the ITGA9 gene. Cytogenetic location: 3p22.2

α5β1, also known as the fibronectin receptor, is an integrin that binds to matrix macromolecules and proteinases and thereby stimulates angiogenesis. It is composed of α5 (ITGA5/CD49e) and β1 (ITGB1/CD29) subunits. It is the primary receptor for fibronectin. The interaction of VLA-5 with fibronectin plays an important role in regulating inflammatory cytokine production by human articular chondrocytes.

<span class="mw-page-title-main">Dermatopontin</span> Protein-coding gene in the species Homo sapiens

Dermatopontin also known as tyrosine-rich acidic matrix protein (TRAMP) is a protein that in humans is encoded by the DPT gene. Dermatopontin is a 22-kDa protein of the noncollagenous extracellular matrix (ECM) estimated to comprise 12 mg/kg of wet dermis weight. To date, homologues have been identified in five different mammals and 12 different invertebrates with multiple functions. In vertebrates, the primary function of dermatopontin is a structural component of the ECM, cell adhesion, modulation of TGF-β activity and cellular quiescence). It also has pathological involvement in heart attacks and decreased expression in leiomyoma and fibrosis. In invertebrate, dermatopontin homologue plays a role in hemagglutination, cell-cell aggregation, and expression during parasite infection.

Fibronectin binding protein A (FnBPA) is a Staphylococcus aureus MSCRAMM cell surface-bound protein that binds to both fibronectin and fibrinogen.

<span class="mw-page-title-main">Arginylglycylaspartic acid</span> Chemical compound

Arginylglycylaspartic acid (RGD) is the most common peptide motif responsible for cell adhesion to the extracellular matrix (ECM), found in species ranging from Drosophila to humans. Cell adhesion proteins called integrins recognize and bind to this sequence, which is found within many matrix proteins, including fibronectin, fibrinogen, vitronectin, osteopontin, and several other adhesive extracellular matrix proteins. The discovery of RGD and elucidation of how RGD binds to integrins has led to the development of a number of drugs and diagnostics, while the peptide itself is used ubiquitously in bioengineering. Depending on the application and the integrin targeted, RGD can be chemically modified or replaced by a similar peptide which promotes cell adhesion.

<span class="mw-page-title-main">Yersiniabactin</span> Chemical compound

Yersiniabactin (Ybt) is a siderophore found in the pathogenic bacteria Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica, as well as several strains of enterobacteria including enteropathogenic Escherichia coli and Salmonella enterica. Siderophores, compounds of low molecular mass with high affinities for ferric iron, are important virulence factors in pathogenic bacteria. Iron—an essential element for life used for such cellular processes as respiration and DNA replication—is extensively chelated by host proteins like lactoferrin and ferritin; thus, the pathogen produces molecules with an even higher affinity for Fe3+ than these proteins in order to acquire sufficient iron for growth. As a part of such an iron-uptake system, yersiniabactin plays an important role in pathogenicity of Y. pestis, Y. pseudotuberculosis, and Y. entercolitica.

<span class="mw-page-title-main">Trimeric autotransporter adhesin</span> Proteins found on the outer membrane of Gram-negative bacteria

In molecular biology, trimeric autotransporter adhesins (TAAs), are proteins found on the outer membrane of Gram-negative bacteria. Bacteria use TAAs in order to infect their host cells via a process called cell adhesion. TAAs also go by another name, oligomeric coiled-coil adhesins, which is shortened to OCAs. In essence, they are virulence factors, factors that make the bacteria harmful and infective to the host organism.

<span class="mw-page-title-main">YadA bacterial adhesin protein domain</span>

In molecular biology, YadA is a protein domain which is short for Yersinia adhesin A. These proteins have strong sequence and structural homology, particularly at their C-terminal end. The function is to promote their pathogenicity and virulence in host cells, though cell adhesion. YadA is found in three pathogenic species of Yersinia, Y. pestis,Y. pseudotuberculosis, and Y. enterocolitica. The YadA domain is encoded for by a virulence plasmid in Yersinia, which encodes a type-III secretion (T3S) system consisting of the Ysc injectisome and the Yop effectors.

Bacterial effectors are proteins secreted by pathogenic bacteria into the cells of their host, usually using a type 3 secretion system (TTSS/T3SS), a type 4 secretion system (TFSS/T4SS) or a Type VI secretion system (T6SS). Some bacteria inject only a few effectors into their host’s cells while others may inject dozens or even hundreds. Effector proteins may have many different activities, but usually help the pathogen to invade host tissue, suppress its immune system, or otherwise help the pathogen to survive. Effector proteins are usually critical for virulence. For instance, in the causative agent of plague, the loss of the T3SS is sufficient to render the bacteria completely avirulent, even when they are directly introduced into the bloodstream. Gram negative microbes are also suspected to deploy bacterial outer membrane vesicles to translocate effector proteins and virulence factors via a membrane vesicle trafficking secretory pathway, in order to modify their environment or attack/invade target cells, for example, at the host-pathogen interface.

<span class="mw-page-title-main">Integrin-like receptors</span>

Integrin-like receptors (ILRs) are found in plants and carry unique functional properties similar to true integrin proteins. True homologs of integrins exist in mammals, invertebrates, and some fungi but not in plant cells. Mammalian integrins are heterodimer transmembrane proteins that play a large role in bidirectional signal transduction. As transmembrane proteins, integrins connect the extracellular matrix (ECM) to the plasma membrane of the animal cell. The extracellular matrix of plant cells, fungi, and some protist is referred to as the cell wall. The plant cell wall is composed of a tough cellulose polysaccharide rather than the collagen fibers of the animal ECM. Even with these differences, research indicates that similar proteins involved in the interaction between the ECM and animals cells are also involved in the interaction of the cell wall and plant cells.

References

  1. ↑ "Invasin". Stedman’s Medical Dictionary. Wolters Kluwer Health.
  2. ↑ Isberg RR, Voorhis DL, Falkow S (August 1987). "Identification of invasin: a protein that allows enteric bacteria to penetrate cultured mammalian cells". Cell. 50 (5): 769–778. doi:10.1016/0092-8674(87)90335-7. PMID   3304658. S2CID   3125395.
  3. ↑ Pepe JC, Miller VL (July 1993). "Yersinia enterocolitica invasin: a primary role in the initiation of infection". Proceedings of the National Academy of Sciences of the United States of America. 90 (14): 6473–6477. Bibcode:1993PNAS...90.6473P. doi: 10.1073/pnas.90.14.6473 . PMC   46954 . PMID   8341658.
  4. ↑ Phan QT, Myers CL, Fu Y, Sheppard DC, Yeaman MR, Welch WH, et al. (March 2007). "Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells". PLOS Biology. 5 (3): e64. doi: 10.1371/journal.pbio.0050064 . PMC   1802757 . PMID   17311474.
  5. ↑ "Invasin: Yersinia enterocolitica". UniProt. P19196. Retrieved 2023-11-28.
  6. ↑ Boyd AP, Cornelis GR (2001). "Yersinia". Principles of Bacterial Pathogenesis. pp. 227–264. doi:10.1016/B978-012304220-0/50007-8. ISBN   978-0-12-304220-0. Invasin (Inv) is a chromosomally encoded outer membrane protein that is expressed in both Y. enterocolitica and Y. pseudotuberculosis.
  7. 1 2 Palumbo RN, Wang C (January 2006). "Bacterial invasin: structure, function, and implication for targeted oral gene delivery". Current Drug Delivery. 3 (1): 47–53. doi:10.2174/156720106775197475. PMID   16472093.
  8. ↑ Sadana P, Geyer R, Pezoldt J, Helmsing S, Huehn J, Hust M, et al. (June 2018). "The invasin D protein from Yersinia pseudotuberculosis selectively binds the Fab region of host antibodies and affects colonization of the intestine". The Journal of Biological Chemistry. 293 (22): 8672–8690. doi: 10.1074/jbc.ra117.001068 . PMC   5986219 . PMID   29535184.
  9. ↑ Brady MF, Yarrarapu SN, Anjum F (2023). "Yersinia Pseudotuberculosis". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   28613468 . Retrieved 2023-11-28.
  10. ↑ Aziz M, Yelamanchili V (2023). "Yersinia Enterocolitica". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   29763012 . Retrieved 2023-11-28.
  11. 1 2 3 PDB: 1CWV ​; Hamburger ZA, Brown MS, Isberg RR, Bjorkman PJ (October 1999). "Crystal structure of invasin: a bacterial integrin-binding protein". Science. New York, N.Y. 286 (5438): 291–295. doi:10.1126/science.286.5438.291. PMID   10514372.
  12. ↑ Dersch P, Isberg RR (March 1999). "A region of the Yersinia pseudotuberculosis invasin protein enhances integrin-mediated uptake into mammalian cells and promotes self-association". The EMBO Journal. 18 (5): 1199–1213. doi:10.1093/emboj/18.5.1199. PMC   1171211 . PMID   10064587.
  13. ↑ Farris E, Sanderfer K, Lampe A, Brown DM, Ramer-Tait AE, Pannier AK (September 2018). "Oral Non-Viral Gene Delivery for Applications in DNA Vaccination and Gene Therapy". Current Opinion in Biomedical Engineering. 7: 51–57. doi:10.1016/j.cobme.2018.09.003. PMC   6474414 . PMID   31011691.
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