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B7. Role of Cell Surface Carbohydrates - Biology

B7. Role of Cell Surface Carbohydrates - Biology


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Cell surface carbohydrates present information-rich binding sites for other molecules and act as "receptors" for biological agents as diverse as viruses, bacteria, toxins, and other cells. There are 3 types:

  1. L-selectins: found on leukocytes ("white" blood cells that are circulating immune cells)
  2. P-selectins: found on activated platelets (which can aggregate to form a type of blood clot) and activated endothelial cells. Activation occurs during the inflammatory response which can lead to the quick movement of pre-formed selectins stored within the cytoplasm to the membrane. In addition, their expression can be induced.
  3. E-selectins: found on activated endothelial cells only after the cells have been induced to form them by certain immune hormones called cytokines releases by immune cells during an inflammatory response.

These selectins are transmembrane proteins with an extracellular CHO binding domain, an EGF-like (epidermal growth factor like) domain, varying numbers of C (complement regulatory) domains, and a transmembrane domain. The extracellular CHO binding domain is found in proteins in all organisms. Proteins that bind carbohydrate motifs are called lectins.

Lectins and CHO ligands
Lectin Family/LectinAbbreviationLigand(s)

Plants

Concanavilin AConAMana1-OCH3
Griffonia simplicifolia lectin 4GS4Lewis b (Leb) tetrasaccharide
Wheat germ agglutininWGANer5Ac(a2->3)Gal(b1->4)GlcGlcNAc(b1->4)GlcNAc
RicinGal(b1->4)Glc

Animals

Galectin-1Gal(b1->4)Glc
Mannose-binding proteinMBP-AHigh Mannose Octasaccahride
Viral
Influenza Virus hemagglutininHANeu5Ac(a2->6)Gal(b1->4)Glc
Polyoma virus protein 1VP1Neu5Ac(a2->3)Gal(b1->4)Glc

Bacterial

EnterotoxinLTGal
Cholera toxinCTGM1 pentasaccharide

In animals, lectins facilitate cell-cell interactions by forming multiple, but weak interactions between the protein and many sugars on the ligand to which it binds.

The selectins are also part of a class of molecules called adhesion molecules. As mentioned for the selectins, adhesion molecules contain

  • an extracellular CHO binding domain (the lectin domain), which mediates binding to adjacent cells or to the extracellular matrix; The P, L, and E selectins can bind a tetrasaccharide containing Sia-Gal-GalNAc-Fuc (called sialyl-Lewisx) on selectin ligand proteins and glycolipids.
  • a transmembrane domain;
  • and a cytoplasmic domain which often interacts with the cytoskeleton within the cell.

The selectins recognize Ser-linked CHO residues (a tetrasaccharide containing sialic acid, galactose, GalNAc and fucose) displayed on transmembrane glycoproteins called selectin ligands. L selectins bind to endothelial cell ligands while P and E selectins bind to ligands on leukocytes. These interactions slow the leukocyte down as it rolls along the surface of the endothelial cells. These interactions involve protein-CHO binding.

This initial binding mediated by selectin-CHO interactions activate the expression of another adhesion molecule on the leukocyte, integrin, a heterodimer with an a and b chain. These cause strong leukocyte-endothelial cell interactions, leading to ultimate movement of the leukocytes through the vessel wall. Other classes of adhesion molecules (in addition to selectins and integrins) are cadherins (calcium-dependent adhesion molecules), and the immunoglobulin-like superfamily (ICAM1, ICAM2, VCAM). VCAM (Vascular Adhesion Molecule) binds the integrin expressed on activated lympocytes, leading to passage of the lympocyte from the lumen of the vessel into the tissues. Integrins appear to bind proteins in the extracellular matrix through RGD (Arg-Gly-Asp) and also through LDV (Leu-Asp-Val) motifs on the proteins, including fibronectin (RGD), thrombospondin (RGD & LDV), fibrinogen (RGD & LDV), van Willebrand Factor (RGD), vitronectin (RGD). They also bind other matrix proteins with an "alpha domain" including collagen and laminin. Integrin/Adhesion molecule interations involve protein/protein interactions.

Genbacev et al. have recently shown that a fertilized egg (in the blastocyst stage which is ready for implantation in the uterine cell wall) express L-selectin which allows a low affinity (rolling-type) interaction of the fertiized egg with the uterine epithelial cells. These cells expressed the CHO ligands on their surface which bind to the L-selectin on the blastocyst. The CHO ligands are only transiently expressed on the surface of the epithelial cells of the uterus, presumably only when the uterus is primed for implantation. After the initial interaction of the blastocyst and epithelial cells, further expression of integrins on the blastocyst surface might result. Problems in any of these molecular steps could result in infertility.

Figure: Endothelial Cell/Leukocyte Interactions: Selectins, Integrins, and ICAMs

An interesting experiment was recently done by Davis et al. that showed the importance of protein modification (like glycoslyslation) to binding and biological function. Post-translational modifications represent one of natures way to change protein function. The researchers were able to chemically modify surface features of a protein to produce new functionalities. They did so by using mutagenesis to change surface amino acids to Cys or replacing Mets with nonnatural amino acid analogs that contain azide or alkyne groups. These modified groups could then direct the location of chemical modifying reagents (such as sugars) to these sites. The researchers studied a pair of proteins involved in inflammation, P-selectin, which binds a transmembrane protein P-selectin-glycoprotein ligand-1, that requires two post-translational changes to bind to P-selectin. They picked a protein completely unrelated to PSGL-1, and selectively modified it using this approach so it contain a glycosylated and a sulfated side chain. The unrelated protein bound to P-selectin.

Selectins: L-selectin | P-selectin | E-selectin | Selectin Ligands

Integrins at a glance

Inner Life of Cell: from Harvard (wait few moment to load) with narration

Integrins: Great Source of Information!

Jmol: Updated P-Selectin Lectin/EGF Domains (IG1Q) Jmol14 (Java) | JSMol (HTML5)

Receptor for Sialic Acids

Lectins that recognize sialic acids, especially members of the Siglec family (sialic acid-recognizing Ig-superfamily lectins) turn out to be important players in our propensity for disease. As we previously discussed, humans lack a hydroxlase gene necessary for the hydroxlation of Neu5Ac to Neur5Gc which is found in chimps who possess the enzyme. Chimp's immune systems seems to confer protection from acquiring simian version of AIDS, cirrhosis, and other diseases which humans acquire when they are infected with the human versions of the HIV virus, hepatitis B or C, or other viruses. These disease and others associated with overactive T cells (rheumatoid arthritis, asthma, type-I diabetes) are not common in chimps. It turns out that there is a link between the type of sialic acid and the expresson of siglics that influences the difference on our disease propensity. Varki et al have shown that chimps and gorillas show much higher levels of expression of Siglecs on T cells, which are critical regulatory and effector cells in the immune system. When siglecs on T cells are activated, T-cell responses are down regulated. Although HIV virus ultimately kills T helper cells, the virus initially activates them on infection, leading to their proliferation and production of a larger number of cells for the virus to infect.

Influenza virus that has caused some of the greatest pandemics in world history also binds to sialic acid on host cells, through a viral binding protein called hemagglutinin. On binding, conformational changes activate a neuraminidase activity of another viral protein, allowing cleavage of the sialic acid glycosidic bond, and subsequent entry of the virus into the cell.


The B7 family of immune-regulatory ligands

The B7 family consists of structurally related, cell-surface protein ligands, which bind to receptors on lymphocytes that regulate immune responses. Activation of T and B lymphocytes is initiated by engagement of cell-surface, antigen-specific T-cell receptors or B-cell receptors, but additional signals delivered simultaneously by B7 ligands determine the ultimate immune response. These 'costimulatory' or 'coinhibitory' signals are delivered by B7 ligands through the CD28 family of receptors on lymphocytes. Interaction of B7-family members with costimulatory receptors augments immune responses, and interaction with coinhibitory receptors attenuates immune responses. There are currently seven known members of the family: B7.1 (CD80), B7.2 (CD86), inducible costimulator ligand (ICOS-L), programmed death-1 ligand (PD-L1), programmed death-2 ligand (PD-L2), B7-H3, and B7-H4. Members of the family have been characterized predominantly in humans and mice, but some members are also found in birds. They share 20-40% amino-acid identity and are structurally related, with the extracellular domain containing tandem domains related to variable and constant immunoglobulin domains. B7 ligands are expressed in lymphoid and non-lymphoid tissues. The importance of the family in regulating immune responses is shown by the development of immunodeficiency and autoimmune diseases in mice with mutations in B7-family genes. Manipulation of the signals delivered by B7 ligands has shown potential in the treatment of autoimmunity, inflammatory diseases and cancer.


B7-H6, an immunoligand for the natural killer cell activating receptor NKp30, reveals inhibitory effects on cell proliferation and migration, but not apoptosis, in cervical cancer derived-cell lines

Background: Although great progress has been made in treatment regimens, cervical cancer remains as one of the most common cancer in women worldwide. Studies focusing on molecules that regulate carcinogenesis may provide potential therapeutic strategies for cervical cancer. B7-H6, an activating immunoligand expressed by several tumor cells, is known to activate NK cell-mediated cytotoxicity once engaged with its natural receptor NKp30. However, the opposite, that is, the effects in the tumor cell triggered by B7-H6 after interacting with NKp30 has not yet been well explored.

Methods: In this study, we evaluated the surface expression of B7-H6 by flow cytometry. Later, we stimulated B7-H6 positive cervical cancer derived-cell lines (HeLa and SiHa) with recombinant soluble NKp30 (sNKp30) protein and evaluated biological effects using the impedance RTCA system for cell proliferation, the scratch method for cell migration, and flow cytometry for apoptosis. Cellular localization of B7-H6 was determined using confocal microscopy.

Results: Notably, we observed that the addition of sNKp30 to the cervical cancer cell lines decreased tumor cell proliferation and migration rate, but had no effect on apoptosis. We also found that B7-H6 is selectively maintained in tumor cell lines, and that efforts to sort and purify B7-H6 negative or positive cells were futile, as negative cells, when cultured, regained the expression of B7-H6 and B7-H6 positive cells, when sorted and cultivated, lost a percentage of B7-H6 expression.

Conclusions: Our results suggest that B7-H6 has an important, as of yet undescribed, role in the biology of the cervical tumor cells themselves, suggesting that this protein might be a promising target for anti-tumor therapy in the future.

Keywords: Apoptosis B7-H6 B7H6 Cell migration Cell proliferation Cervical cancer.


Overview of the role of kinetoplastid surface carbohydrates in infection and host cell invasion: prospects for therapeutic intervention

Kinetoplastid parasites are responsible for serious diseases in humans and livestock such as Chagas disease and sleeping sickness (caused by Trypanosoma cruzi and Trypanosoma brucei, respectively), and the different forms of cutaneous, mucocutaneous and visceral leishmaniasis (produced by Leishmania spp). The limited number of antiparasitic drugs available together with the emergence of resistance underscores the need for new therapeutic agents with novel mechanisms of action. The use of agents binding to surface glycans has been recently suggested as a new approach to antitrypanosomal design and a series of peptidic and non-peptidic carbohydrate-binding agents have been identified as antiparasitics showing efficacy in animal models of sleeping sickness. Here we provide an overview of the nature of surface glycans in three kinetoplastid parasites, T. cruzi, T. brucei and Leishmania. Their role in virulence and host cell invasion is highlighted with the aim of identifying specific glycan-lectin interactions and carbohydrate functions that may be the target of novel carbohydrate-binding agents with therapeutic applications.

Keywords: Carbohydrate-binding agents Leishmania Trypanosoma brucei Trypanosoma cruzi kinetoplastids lectins surface glycans.

Figures

Scheme of the interplay between…

Scheme of the interplay between T. cruzi surface glycans and mammalian host cells.…

Immunomodulatory events mediated by glycans…

Immunomodulatory events mediated by glycans during infection with T. brucei . VSGs interact…

Schematic representation of the major…

Schematic representation of the major parasite–macrophage interactions mediated by surface glycans in Leishmania…


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How do carbohydrates help in cell to cell recognition?

Cell&ndashcell recognition occurs when two molecules restricted to the plasma membranes of different cells bind to each other, triggering a response for communication, cooperation, transport, defense, and/or growth.

Furthermore, what is the role of membrane carbohydrates in cell cell recognition? Membrane carbohydrates perform two main functions: participate in cell recognition and adhesion, either cell-cell signaling or cell-pathogen interactions, and they have a structural role as a physical barrier.

In this regard, how are carbohydrates used in cell recognition?

Recognition and adhesion. The surface carbohydrates on a cell serve as points of attachment for other cells, infectious bacteria and viruses, toxins, hormones, and many other molecules. The carbohydrates are recognized by the cell adhesion molecules which are glycoproteins expressed on the cell surface.

How do glycolipids and glycoproteins help in cell to cell recognition?

Lipid and proteins on the cell membrane surface often have short carbohydrate chains protruding out from the cell surface, known as glycolipids and glycoproteins. Glycoproteins can also serve as antigens, which are used in allowing cells to recognize each other.


Dendritic Cells

Immune Response Activation and Co-stimulation

The interactions between CD80 /86 on APCs and CD28 on T cells results in powerful co-stimulation. CTLA-4 is a negative regulator expressed at the surface of T cells. CTLA-4–Ig fusion protein, which binds CD80/CD86 at the surface of APCs, is actively being used to block the CD28-mediated co-stimulatory pathway in order to inhibit the activation of CD28-expressing T cells and contain the T cell–mediated autoimmune response. The agonist CTLA-4–Ig has been used successfully in RA, whereas anti–CTLA-4 antibodies are approved to treat advanced melanoma. It is possible that other co-stimulatory pathways may be amenable to manipulation in the treatment of autoimmune diseases, such as PD-1 and others. A final approach is to target immune cells with antibodies to induce their depletion in this way, an antibody against CD52, which is expressed on lymphoid and myeloid cells, or against CD19 and CD20, which are expressed by B cells, may ultimately show effects in certain conditions.


Carbohydrates in Drug Discovery and Development

Carbohydrates in Drug Discovery and Development: Synthesis and Applications examines recent and notable developments in the synthesis, biology, therapeutic, and biomedical applications of carbohydrates, which is considered to be a highly promising area of research in the field of medicinal chemistry. Their role in several important biological processes, notably energy storage, transport, modulation of protein function, intercellular adhesion, malignant transformation, signal transduction, viral, and bacterial cell surface recognition formulate the carbohydrate systems to be an exceedingly considerable scaffold for the development of new chemical entities of pharmacological importance. In addition to their easy accessibility, high functionality and chiralpool characteristics are the few additional fascinating structural features of carbohydrates, which further enhance their utilities and thus they have been able to attract chemists and biologists toward harnessing these properties for the past several decades.

This book covers an advanced aspect of carbohydrate-based molecular scaffolding, starting with a general introduction followed by a detailed discussion about the impact of diverse carbohydrate-containing molecules of great therapeutic values and their impact on drug discovery and development. The topics covered in this book include the significance of heparin mimetics as the possible tools for the modulation of biology and therapy, chemistry and bioactivities of C-glycosylated compounds, inositols, iminosugars, KDO, sialic acids, glycohybrids, macrocycles, plant oligosaccharides, anti-bacterial and anti-cancer vaccines, antibiotics, and more.

Carbohydrates in Drug Discovery and Development: Synthesis and Applications examines recent and notable developments in the synthesis, biology, therapeutic, and biomedical applications of carbohydrates, which is considered to be a highly promising area of research in the field of medicinal chemistry. Their role in several important biological processes, notably energy storage, transport, modulation of protein function, intercellular adhesion, malignant transformation, signal transduction, viral, and bacterial cell surface recognition formulate the carbohydrate systems to be an exceedingly considerable scaffold for the development of new chemical entities of pharmacological importance. In addition to their easy accessibility, high functionality and chiralpool characteristics are the few additional fascinating structural features of carbohydrates, which further enhance their utilities and thus they have been able to attract chemists and biologists toward harnessing these properties for the past several decades.

This book covers an advanced aspect of carbohydrate-based molecular scaffolding, starting with a general introduction followed by a detailed discussion about the impact of diverse carbohydrate-containing molecules of great therapeutic values and their impact on drug discovery and development. The topics covered in this book include the significance of heparin mimetics as the possible tools for the modulation of biology and therapy, chemistry and bioactivities of C-glycosylated compounds, inositols, iminosugars, KDO, sialic acids, glycohybrids, macrocycles, plant oligosaccharides, anti-bacterial and anti-cancer vaccines, antibiotics, and more.

Key Features

• Presents a practical and detailed overview of a wide range of carbohydrate systems including KDO, sialic

acids, inositols, iminosugars, etc relevant for drug discovery and development.

• Highlights the use of functionalized carbohydrates as synthons for the construction of various systems.

• Covers recent developments in the synthesis of various glycohybrid molecules and vaccines.

• Highlights the significance of heparin mimetics as tools for the modulation of biology.

• Provides an impact of glycan microarrays and carbohydrate– protein interaction.

• Presents a practical and detailed overview of a wide range of carbohydrate systems including KDO, sialic

acids, inositols, iminosugars, etc relevant for drug discovery and development.

• Highlights the use of functionalized carbohydrates as synthons for the construction of various systems.

• Covers recent developments in the synthesis of various glycohybrid molecules and vaccines.

• Highlights the significance of heparin mimetics as tools for the modulation of biology.

• Provides an impact of glycan microarrays and carbohydrate– protein interaction.


B7. Role of Cell Surface Carbohydrates - Biology

AD6, a mutant derived from 3T3 Balb/c cells, is characterized by low adhesion to substratum, round shape, increase in surface microvilli, increase in agglutinability by concanavalin A, and loss of directional motility. These properties are often observed in transformed cells. However, the mutant has normal growth properties and anchorage-dependence of growth, and it does not form tumors. In AD6, the biosynthesis of complex carbohydrates and glycoproteins is impaired because of a block in the acetylation of GlcN-6-P. This defect is responsible for all the surface alterations because feeding of GlcNAc to AD6 cells corrects the defects in the synthesis of complex carbohydrates and the exposure of glycoproteins at the outer surface of the plasma membrane. Parallel to this biochemical reversion, there is full restoration of the altered biological properties. In contrast, GlcNAc has no effect on the morphologic features of two lines of transformed cells. Our results suggest that the carbohydrate portion of cell surface proteins has an important role in adhesion and related aspects of cell behavior. The fact that a defined alteration of the cell surface induces many properties often encountered in transformed cells, without affecting control of cell division, strongly suggests that these alterations in properties are not sufficient to account for the loss of growth regulation.


Describe the biological significance of carbohydrates.

Carbohydrates play a vital role in a living being. Its importance can be studied under the following headings:

1. Storage role: Carbohydrates serve as the storage of metabolic fuel for a living organism. For example, starch and glycogen are present as the storage form in plants and animals respectively. The storage form is broken down into glucose units which serve to provide energy.

2. Structural role: Carbohydrates like cellulose, hemicellulose, and lignin provide a mechanical and protective function to the cell wall of plants. It also provide a definite shape to the plant cell. Chitin forms the part of the exoskeleton in insects and crustaceans.

Glycosaminoglycan like hyaluronic acid, heparin, chondroitin sulfate, and dermatan sulfate is a part of an extracellular matrix that plays a structural role in bacteria and animals only. It is a unit of acidic sugar and amino sugar.

3. Communication role: Carbohydrates are covalently bound to either protein or lipid to form glycoproteins or glycolipids. Glycoproteins act as a hormone (Thyroid-stimulating hormone (TSH) and erythropoietin), enzyme (Phosphatase, lipase, pepsinogen), receptor, integral membrane protein, mucins, and Cadherin is the major adhesion molecule.

Glycolipid acts as an enzyme, immunoglobins, secretory proteins, and membrane proteins.



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