Class Of Type 1 Transmembrane Proteins Biology Essay

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Cadherins (Calcium dependent adhesion molecules) are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. (8) They are dependent on calcium (Ca2+) ions to function. Cadherins can be classified into several subfamilies: the type I (classical) and type II cadherins, which are linked to the actin cytoskeleton the desmosomal cadherins (desmocollins and desmogleins), which are linked to intermediate filaments and the protocadherins, which are expressed primarily in the nervous system. In structure, they share cadherin repeats, which are the extracellular Ca2+-binding domains. There are multiple classes of cadherin molecule, each designated with the type of tissue it's associated with. (6)

Image

Figure 1. Schematic diagram of the domain organization of various cadherin subfamilies. Cadherins are characterized by the presence of cadherin sequence repeats of about 110 amino acids, which form independently folded domains.(Science Direct,2003)(6)

Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the extracellular matrix (ECM). They also play a role in cell signalling and by this means they define cellular shape and mobility. (8) Integrins inform a cell of the molecules in its environment and the cell evokes a response. Not only do integrins perform this outside-in signalling, but they also operate an inside-out mode. Therefore, they transduce information from the ECM to the cell as well as reveal the status of the cell to the outside, allowing rapid and flexible responses to changes in the environment. (8)

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Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Cell adhesion molecules are membrane-spanning proteins responsible for both cell junctions and for passing cell adhesions. Cell Adhesion Molecules (CAMs) are proteins located on the cell surface that are involved with the binding with other cells or with the extracellular matrix (ECM) in the process called cell adhesion. Adhesion molecules on the surface of eukaryotic cells allow cells to interact with each other and the extracellular matrix. Structures formed by cell adhesion molecules allow cells to regulate extracellular interactions and allow for communication between cells and the surrounding environment. Major cell adhesions are: cadherins responsible for cell-cell junction such as adherins junctions and desmosomes. Integrins- primary found in cell-matrix junctions. (1)

Cell junctions can be grouped into three categories: gap junctions, tight junctions and anchoring junctions. Gap junctions allow direct cell-cell communication. Tight junctions are close up junctions that block movement of materials between cells. Anchoring junctions hold cells to one another and to extracellular matrix. (1)

Figure 2. Diagram showing the different junctions taken from: (Danton H. O'Day, 2009) (5)

As indicated in the figure, groups of junctions including tight and adherens junctions and desmosomes make up junctional adhesion complexes. These junctional adhesion complexes provide strong binding between these cells. They also mediate intercellular communication and play a critical role in cell polarity. Cadherins are involved in cell-cell adhesion as part of desmosomes and adherens junctions while integrins mediate cell-substratum adhesions via hemi-desmosomes and focal adhesions. (5)

CADHERINS

Cadherins are calcium-dependant adhesion molecules which extra-cellularly can attach to other cadherins if homophilic. Cadherins are also a family of homotypic meaning that one cadherins binds to a similar cadherins on another cell. Because they can bind to another cell they are suited to their primary function of maintaining adhesion between similar cells within a tissue. Cadherins are found in several membrane structures, including adherins functions, desmosomes, tight junctions, and gap junctions. There are two major types of cadherins: E-cadherins (classic) found in the adherens junction and desmosomal cadherins found in the desmosomes. These are linked with keratin intermediate filaments and the desmoplakins of the cytoplasmic plaques. Keratin intermediate filaments form junctions that hold cells together (desmosomes), or attach cells to matrix (hemidesmosomes). E- Cadherins are a family of proteins called catenins mediates binding of the cytoplasmic tail of cadherins to the cytoskeleton. Β- Cadherins bind directly to the cytoplasmic tail of classic cadherins and to the protein α- cadherins. F-acting microfilaments bind to α-catenin to complete the linkage. E-cadherins are further divided into type 1 and type II. Type 1 cadherins include E-, P-, and N-cadherins and are expressed in epithelial cells. Type II include several cadherins and have been designated cadherins 5-to 12. A desmosome holds adjacent cells together tightly. Desmosomes are distinguished by the dense plaques of intermediate filaments. Intermediate filaments play a structural role in cells. They increase the resistance of cells to mechanical forces and help hold together sheets of epithelial cells. There are two major groups of desmosomal cadherins- the desmogleins and desmocolllins. These proteins are found in specialized cell-cell junctions called desmosomes. The cytoplasmic domains of these proteins interact with intermediate filaments through plaque protein, called desmoplakin and plakogloblin. Cadherins are simple transmembrane glycoprotein's involved in maintaining intercellular connections through homophilic binding. The cytoplasmic domain of cadherins is linked to cellular parts of cadherins, proteins that are necessary for cadherins function. Cadherins function in cell-cell adhesion by clustering on the plasma membrane to form adhesion junctions. Interactions between cells involve the N-terminal cadherins repeat domain, generating a "cadherins zipper", on which the strength depends on the number of cadherins molecules involved in the adhesion junction. The cadherins are also important in cell-cell signal transduction. The adhesive and signalling events mediated by cadherins are particularly important for coordinating cell functions during embryonic development as well as in adult tissues. They act as both receptor and ligand and are responsible for the selective cell-cell adhesion which is necessary to allocate different cell types to their proper positions during development. Cadherins consist of five tandem repeated extracellular domains, a single membrane-spanning segment and a cytoplasmic region. Cadherins depend on calcium for their function: removal of calcium abolishes adhesive activity and renders cadherins vulnerable to proteases. (2)(9)

Type of Cadherin

What tissues?

Structure:

Intracellular binding proteins

Cytoplasmic   filaments

E-Cadherin;

P-Cadherin

epithelial cells

adhesion belts

catenins,   alpha actinin

actin

Desmosomal Cadherin

epidermis and placenta

desmosomes

desmoplakins I, II; Plakoglobin

keratin; desmin 

N-Cadherin

nerve, muscle, lens cells

adhesion belts

catenins, alpha actinin, vinculin

actin

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Figure 3. Different types of cadherins (Childs, G, 1998)

C:\Users\Mandy\Pictures\ch19f29 cad.jpgFigure 4. The linkage of classical cadherins to actin filaments (

Molecular biology of the cell, 2002)

INTEGRINS

Integrins are adhesion molecules involved in cell-cell- matrix adhesions, particularly in the hemidesmosomes of basal keratinocytes and cultured keratinocytes. Integrins are heterodimers with an alpha and beta chain. An integrin molecule is composed of two noncovalently associated transmembrane glycoprotein subunits called α and β as shown in figure 5. Integrins are also membrane-spanning proteins that link the cytoskeleton to extracellular matrix proteins or ligands; involved in wound repair, immune cell adhesion and recognition, and cell movement during development. There are a number of different matrix proteins to which integrins bind. β1 subunits form dimers with at least 12 distinct α subunits. The β2 subunits form dimers with at least four types of α subunit. They are expressed on the surface of white blood cells, where they have an essential role in enabling these cells to fight infection. The β2 integrins mainly mediate cell-cell rather than cell-matrix interactions, binding to specific ligands on another cell, such as an endothelial cell. The β3 integrins are found on a variety of cells, including blood platelets. They bind several matrix proteins, including fibrinogen. Integrins function as transmembrane linkers that connect extracellular matrix molecules to actin filaments in the cell cortex and thereby regulate the shape, orientation, and movement of cells. Integrins form adhesive structures with extra-cellular matrix known as focal adhesion. Focal adhesion can transmit force applied to the outside of the cell across the cell membrane. Focal adhesions are sites where transduction of mechanical signals from the extracellular environment occurs. The clustering of integrins at the sites of contact with the matrix (or with another cell) can also activate intracellular signalling pathways. Integrins are also important molecules in cell-matrix signalling events. Binding of integrins to the extra cellular matrix triggers an intercellular signalling cascade that can result in altered gene expression. (2)(7)

C:\Users\Mandy\Pictures\ch19f64.jpgFigure 5. The subunit structure of an integrin cell-surface matrix receptor (Molecular biology of the cell, 2002)

INTEGRIN

LIGAND*

DISTRIBUTION

α5β1

fibronectin

ubiquitous

α6β1

laminin

ubiquitous

α7β1

laminin

muscle

αLβ2 (LFA-1, see p. 1411)

Ig superfamily counterreceptors

white blood cells

α2β3

fibrinogen

platelets

α6β4

laminin

epithelial hemidesmosomes

Figure 6. Different types of integrins (Molecular biology of the cell, 2002)

Hemidesmosomes: Are sites of connections at the base of an epithelial cell with the matrix. The cartoon below shows the components.  Intermediate filaments are stuck in a plaque (like the desmosome plaque) and Integrins molecules (receptors for matrix proteins) help connect the site with the matrix. (3)

C:\Users\Mandy\Pictures\hemidesmosome.gif

Figure 7. Hemidesmosomes (Childs, G, 2001)

Desmosomes: Two plaques on adjacent cells (containing desmoplakin and other proteins) are connected by cadherin molecules.  These molecules are linked by calcium.  The intermediate filaments loop into the plaques spreading out into the cytoplasm.  This links two cells together structurally. (3)

C:\Users\Mandy\Pictures\desmosome.gif

Figure8. Desmosomes (Childs, G, 2001)