Contactins: structural aspects in relation to developmental functions in brain disease.

The contactins are members of a protein subfamily of neural immunoglobulin (Ig) domain-containing cell adhesion molecules. Their architecture is based on six N-terminal Ig domains, four fibronectin type III domains, and a C-terminal glycophosphatidylinositol (GPI)-anchor to the extracellular part of the cell membrane. Genetics of neuropsychiatric disorders, particularly autism spectrum disorders, have pinpointed contactin-4, -5, and -6 (CNTN4, -5, and -6) as potential disease genes in neurodevelopmental disorders and suggested that they participate in pathways important for appropriate brain development. These contactins have distinct but overlapping patterns of brain expression, and null-mutation causes subtle morphological and functional defects in the brain. The molecular basis of their neurodevelopmental functions is likely conferred by heterophilic protein interactions. Cntn4, -5, and -6 interact with protein tyrosine phosphatase receptor gamma (Ptptg) using a shared binding site that spans their second and third Ig repeats. Interactions with amyloid precursor protein (APP), Notch, and other IgCAMs have also been indicated. The present data indicate that Cntn4, -5, and -6 proteins may be part of heteromeric receptor complexes as well as serve as ligands themselves.