13.12: Ig Superfamily CAMs

In addition to occludin and claudins, junction adhesion molecules (JAMs) have recently been found in tight junctions. These molecules are members of a gigantic superfamily of cell adhesion molecules known as the Ig (immunoglobulin domain) superfamily because all of these proteins contain an immunoglobulin loop domain that plays an important part in the adhesion mechanism. The purpose of immunoglobulins (antibodies) is to recognize and adhere to other molecules, so it makes sense that such a structural motif would also be used for other kinds of adhesion. Ig loops fall into two primary categories, again based on the loops of an immunoglobulin molecule. These are the variable (V) loop and the constant (C1) loop. Some IgSF molecules contain a C2 loop, which has amino acid homology to the V loop, but structural/size similarity to the C1 loop. The size of IgSF molecules ranges greatly, and the number of Ig loop domains and other domains (e.g. fibronectin Type III domains) can also vary significantly.

Figure \(\PageIndex{15}\). Ig superfamily cell adhesion molecules NCAM, P0, and L1 (top to bottom) are built with fibronectin Type II domains and Ig C2-like domains.

IgSF molecules are involved in a number of cellular processes requiring adhesion. The most obvious, of course, is the immune response in which an immunoglobulin, either secreted or on a cell, binds to a molecule foreign to the body. However, there are many other interactions outside of the immune system that involve IgSF molecules. One well-studied area is in neural development, where IgSF members L1 (L1CAM), NCAM and numerous others are expressed in specific patterns to control the routing of axons as they make their way from the neuronal cell body to their eventual connections. This path can often be very long, crossing many different cell types, and taking several turns, so a robust guidance system is crucial to make a normal functioning nervous system. Specific combinations of cell adhesion molecules (also called axon guidance molecules in this case) direct these processes even through the extraordinary density of potential (but incorrect) nerve cell targets in the brain. IgSF molecules have been found to bind both homophilically and heterophilically, and for that matter, not just to other IgSF molecules, but to adhesion molecules of other structural families such as integrins.