Cell Adhesion Proteins

 Cell Adhesion Proteins Background

Cell Adhesion in General

Cell adhesion was first identified in sponges in 1907 by Wilson. Since then, cell adhesion has been found to be critical for cellular function and organism survival. It is seen in processes such as: inflammation, cell growth, proliferation, gene regulation, differentiation, apoptosis and migration.

Cell adhesion systems have similar structural and functional roles throughout the eukaryote kingdom. In 1957, Moscona first found mammals and birds share similar molecular characteristics and binding sites for cell adhesion. Later, more cell adhesion proteins in higher eukaryotes were found to share structural and functional similarities to lower organisms. However, structural flexibility of each individual cell adhesion molecules determines the specific binding characteristics of the proteins.

Cell adhesions in higher organism are mediated by multiple systems. Study of cell adhesion in lower organisms could provide information for understanding the complexity of the adhering systems in higher organisms. For example: Drosophila melanogaster is one of the model systems to study cell adhesion. This system contains major classes of cell adhesion molecules including Notch/Delta, immunoglobulin homologs, Fasciclin IV, Fasciclin I, Leucine-rich repeat proteins (LRRS), cadherins, integrins, etc. C. elegans has simpler cell adhesion systems than Drosophila. In this system, adhesions of the neighboring cells are required for the determination of cell fate. Sexual agglutination in S. cerevisiae, a unicellular eukaryote, could be the simplest model cell adhesion system for both fungi and mammals. For example: α-agglutinin is a member of the immunoglobulin superfamily. It has sequence similarities to cell adhesion molecules in the ALS family in yeast Candida albicans and other members in the Ig superfamily, which is one of the major classes of cell adhesion molecules in mammalian systems.


Structural Characteristics of Cell Adhesion proteins

Cell adhesion proteins are usually glycoproteins that mediate cell-cell and cell extracellular matrix recognition at the extracellular surface. Most cell adhesion molecules have similar conformations in their adhesive domains. For example: the adhesive domains of cadherin, Immunoglobulin like, fibronectin type III and EGF are predominantly β-sheet structures. The common motif involved in cell adhesion is the Greek key barrel structure containing one or two anti-parallel β sandwiches.

Ig-like domains are a major class of Greek key barrel domains. They have sequence similarities to the variable or constant domain of antibodies containing seven to nine anti-parallel β strands. The anti-parallel P sheets form a 3-D β-barrel. Ig-like domains are stabilized by hydrophobic core and disulfide bonds. They are divided into two major sets: Ig C-like and Ig V-like domains.


Functionally Related Structural Characteristics of Cell Adhesion Proteins

Cell adhesion proteins have functional diversity. Interaction of cell adhesion molecules could be homophilic or heterophilic protein-protein interactions or protein-carbohydrate interactions. Structural changes of the cell adhesion molecules are often related to their functional properties.

Homophilic Protein-Protein Interactions. For example, cadherins are transmembrane Ca2+-dependent homophilic adhesion molecules. Cadherins are responsible for maintenance of the junctions between similar cells in tissues. Cell-cell adhesion is mediated through the N-terminal domain of the cadherins. It contains five similar extracellular domains EC1 to EC5. X-ray crystallographic studies in N-cadherin showed that EC1 domain forms a dimer, in which the monomers are oriented in parallel with their adhesive binding surface pointing outward from the plasma membrane. The monomer units of EC1 domains interact with each other in an antiparallel way, using their adhesive binding surfaces and forming a β-barrel structure. A putative interface of the interaction was suggested to have both hydrophobic and polar/charged character that mimics the interface of the interaction of immunoglobulin domains with one another in the Ig superfamily.

Heterophilic Protein-Protein Interactions. For example, binding of the integrins to various cell surface receptors and extracellular matrix ligands is a major class of heterophilic protein-protein interaction in cell adhesion systems. Upon binding to soluble fibrinogen, the integrin αIIbβ3 is converted to a high affinity binding state. The conformational changes of the integrin induced by ligand binding in this case are critical for its adhesive activity. Binding of a T-cell receptor can also modulate the binding affinity of the integrin, leukocyte function associated antigen- 1 (LFA-1), to its receptors such as ICAM-l or ICAM-2 (intercellular cell adhesion molecule). Binding of ICAM-l can further induce conformational changes of LFA-1. The adhesive binding site of the protein is located in the C-terminal of LFA-l based on X-ray crystallographic study.

A tripeptide, arginine-glycine-aspartic acid (RGD), is a common integrin ligand binding motif. For example, the integrin binding ligand type III module of fibronectin has a Greek key barrel structure, whose RGD motif, located at the apex of the loop connecting F and G β strands, mediates adhesion. Straightening of the RGD-loop into a more linear fluctuating conformation by unfolding reduces the accessibility of the loop to the surface bound integrins, and therefore decreases the affinity and selectivity of binding.

Protein-Carbohydrate Interactions. The selectins are important in lymphocyte and neutrophil interaction with vascular endothelium. The selectins are adhesion molecules that bind to carbohydrates. There are not yet any direct structural data on the binding of selectins to carbohydrates. The selectins binds carbohydrates with low affinity and have very fast on and off rates.