Adhesion molecules

The following is a summary of information that is designed to "supplement" that in your book.  

Cell to Cell Binding

Calcium dependent adhesion molecules (Cadherins)

Over a dozen different types.
Almost all vertebrate cells express one or more cadherins
Single-pass transmembrane glycoprotein composed of about 700-750 residues
Extracellular domains:
contain about 100 amino acid residues
contain calcium binding sites
bind in a homophilic pattern, i.e. one cadherin binds to another in the extracellular space
connects cells together at specialized junctions
may mediate interactions between the cells' actin cytoskeletons
a sequence His-Ala-Val may be involved in the actual "homophilic" binding.
Intracellular domain binds to specific proteins in the cytoskeletal system.




Well known types of Calcium dependent adhesion molecules:

Type of Cadherin What tissues? Structure: Intracellular binding proteins Cytoplasmic   filaments
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

Cell to Cell Surface Carbohydrate Binding Proteins (Selectins)

Transient transmembrane binding proteins (lectins).
In the presence of Calcium, bind to specific oligosaccharides on another cell
"Heterophilic" cell adhesion (binding protein binds to another type of site on a cell
P-Selectins allow the initial binding of  white blood cells to endothelial cells
Local chemical mediators at the site of inflammation signal the endothelial cells to express P-selectin.
Nearby neutrophils express the oligosaccaride on both the glycolipids and glycoproteins in their membrane.
Thus, they are bound at this inflammatory site by the endothelial cells
Binding is relatively weak and the cells roll along the endothelial cell until they bind more tightly by their integrins (see below). Integrin binding is tighter and stimulates the cell to crawl out of the blood vessel.

Cell to Cell binding through special Integrins

Integrins are also transmembrane binding glycoproteins that usually bind cells to matrix.
However, they also may bind cells to cells.
Binding is calcium dependent.
Binding is from an integrin to a specific ligand on the target cell
Binding may involve actin filaments, but is not associated with a cell junction
Integrins contain an alpha and a beta subunit: Most cell to cell interactions involve integrins with an alpha and a beta-2 subunit
Integrins on white blood cells allow tighter binding to endothelial cells before they migrate out of the blood stream to tissue.  LFA-1 (white blood cells); Mac-1 (macrophages)
Humans with a genetic disease called "leucocyte adhesion deficiency" are unable to synthesize the Beta-2 subunit.  Thus, the white blood cells lack the entire family of beta-2 receptors needed to bind to  endothelial cells.   They suffer repeated bacterial infections

Non-Calcium dependent Cell to Cell binding

Belong to the immunoglobulin (Ig) superfamily; NCAM's, ICAMs and L1 are examples
Single pass, transmembrane proteins which may bind to the cytoskeletal system inside the cells
Outside the cell, the binding may be homophilic (to each other) or heterophilic (to another molecule)
Cells may have N-CAMs and Cadherins, but the N-CAM binding is not as strong as the cadherin binding
N-CAM (neural cell adhesion molecule) is actually expressed by a variety of cell types., including nerve cells; binds by homophilic interactions
ICAM (intercellular adhesion molecules) may be expressed on activated endothelial cells. Theseare  the target ligand for the integrins expressed by white blood cells (heterophilic binding)
L1 is a neural cell to cell adhesion molecule important in developing nerve processes

Cell to Matrix Binding: Integrins

Cells can be influenced heavily by the environment (matrix proteins) because of the presence of transmembrane glycoproteins called Integrins.

Extracellular matrix receptors that have selective affinity for certain matrix proteins
Bind with relatively low affinity (Ka= 106-109 liters/mole):  this provides a "velcro effect" that allows cells to explore their environment
Binding is calcium and magnesium dependent. Extracellular site is with a ligand in the matrix
Intracellular site may be with proteins associated with the actin cytoskeleton (talin and alpha actinin); some integrins bind to intermediate filaments, however
Integrins have an alpha and a beta subunit (heterodimer). 
Subunits can be diverse (different types) by alternative splicing
Specificity of binding depends on the combination of alpha and beta subunits
Cells with alpha-6, beta-4 integrins have hemidesmosomes.  Bind matrix proteins in the basal lamina (like laminins) and intermediate filaments, like keratins, in the cytoplasm
White blood cells have alpha1 and beta 2 integrins that bind to endothelial cells
Macrophages have alpham and beta 2 integrins that also bind to endothelial cells.
Platelets have beta 3 subunit in their integrins that allows them to bind fibrinogen during blood clotting
Humans with Glanzmann's disease are genetically deficient in beta 3 containing integrins
These patients bleed excessively
Cells with alpha 5 and beta 1 integrins bind fibronectin in the extracellular matrix

Last updated: 06/04/01
copyright 1998 Gwen V. Childs, Ph.D.
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