Adhesion Molecule Proteins

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 Adhesion Molecule Proteins Background

Cell Adhesion Molecules (CAMs) are subdivided into four families such as selectins and their mucin family ligands, integrins and immunoglobulin superfamily (IgSF) molecules, which mediate different steps in leukocyte adhesion and emigration.



The selectins consist of three different glycoproteins which share the common presence of an NH2-terminal C-type (Ca2+ dependent) lectin binding domain, an epidermal growth factor like region (EGF) and a variable number of short consensus repeat motifs (SCR) which are related to those in complement regulatory proteins. The variability in number of SCR motifs ultimately leads to different physical lengths of the selectin protein which likely functions to place the lectin binding domain of the selectins at varying distances from the cell surface. All types of currently described selectins also share homologous transmembrane spanning regions and contain a short intra-cytoplasmic region which, like intra-cytoplasmic regions of other CAMs, interacts with the microfilament component of the cytoskeleton and function in cellular signaling including activation. The ligand binding activity of selectins is primarily at the lectin-binding domain with a variable contribution from EGF and SCR domains. Selectin-ligand interactions are responsible for the initial contact of leukocytes with the vascular endothelium.

The three types of selectins (E-selectin or CD62E, L-selectin or CD62L and P-selectin or CD62P) recognize and bind to a diverse array of sulfated, sialylated and/or frxcosylated carbohydrates, which extend from a protein backbone. The prototypic selectin ligand is a fucosylated tetrasaccharide sialyl Lewisa (sLea or CD 15s) and its related isomer sialyl Lewisa (sLea or CD 15a). These ligands and other fucosylated lactosamines are highly expressed on glycoproteins of PMNLs and monocytes concentrated on the microvilli and are also expressed on natural killer cells and on activated lymphocytes.



Integrins are a family of more than 30 structurally homologous heterodimeric transmembrane proteins that are responsible for cell to cell, cell to matrix and cell to soluble substances (e.g., fibrinogen) interactions. Each integrin heterodimer is composed of two polypeptide subunits, α and β, which are non-covalently associated. Currently, 15 α subunits and 9 β subunits have been identified and theoretically these 24 subunits could associate toform 135 different αβ dimers. The actual number of integrin dimers expressed on cells is much less than this number, at around 20. This is due to restricted association of α subunits with a small selection of the β subunits, in many cases just one (e.g. αMβ2). There do exist, however, α subunits which can associate with more than one β subunit (e.g., α4βl and α4β7) and one β subunit can associate with many α subunits.

A t the amino terminus of the integrin chain, there is a globular binding domain which has been shown to contribute to inter-chain non-covalent association and to ligand binding. Integrin a-subunit chains have three or four repeats of a divalent cation-binding motif which binds Ca2+, Mg2+, or Mn2+. The presence of these cations is necessary for both subunit structure and function. Additionally, in the leukocyte β2 integrins (LFA-1, MAC-1, and P150,95) as well as one β1 integrin, VLA-2 (α2β1), there exists a 200 amino acid domain not present on other integrins. This "I" (for inserted) domain represents an additional metal binding site and is essential for substrate recognition by the integrins in which it is present. It is likely that globular binding sites of the associated α and β chains interact toform a single three dimensional ligand binding pocket.


Immunoglobulin Superfamily Molecules

The immunoglobulin superfamily (IgSF) is a large group of transmembrane glycoproteins with multiple extracellular disulfide bonded loops. These regions are homologous to ones in immunoglobulin molecules. IgSF molecules are 70-110 amino acids and associate with their ligands in a Ca2+-independent manor. There are two major types of IgSF: the C1-type is responsible for antigen recognition and the C2-type is responsible for non-antigen specific functions such as cell adhesion. Members of the latter type have a variable number of extracellular Ig-like domains with conserved cysteine residues which form intra-chain disulfide bonds to stabilize the β-sheets of the tertiary structure. Five members of the C2-type of IgSF mediate leukocyte adhesion and these are expressed on endothelium: ICAM-1 (CD54), ICAM-2(CD 102), VCAM-1 (CD106), PECAM (CD31), and MadCAM-1.


Cell Adhesion Molecules in the Leukocyte Adhesion Cascade

The recruitment of leukocytes from the blood stream to extravascular sites of inflammation is necessary for an effective inflammatory response. The recruitment is mediated by Cell Adhesion Molecules, cytokines and chemoattractants which together coordinate this complex series of events. The adhesion cascade involves five steps which occur in sequence but may overlap in time. At sites of inflammation in the systemic circulation (as opposed to the pulmonary circulation), post-capillary venule endothelium becomes activated by the local generation of a variety of inflammatory mediators. Histamine, thrombin and LTC4 lead to a rapid expression of P-selectin on the endothelial surface while the early proinflammatory cytokines such as IL-1 and TNFα lead to de novo synthesis of both P- and E-selectin as well as ICAM-1 and VCAM-1 resulting in increased surface expression at time points greater than 2 hours following stimulation. When endothelium is exposed to these cytokines especially in the presence of FN for prolonged periods (as during chronic infection), the volume of the endothelial cell expands and it becomes columnar, similar to the morphology in high endothelial venules in lymph nodes.