APP∙CNTN Complex Architecture is Conserved Throughout the Vertebrate Lineage
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Abstract
Contactins (CNTNs) are a group of up to six cell adhesion molecules (CAMs) of the immunoglobulin (Ig) superfamily found throughout the metazoan lineage. CNTN architecture is broadly conserved, and these proteins are composed from the N-terminus of six Ig domains linked to four fibronectin type III (FN) domains. The C-terminal FN-4 domain terminates with a glycosylphosphatidylinositol (GPI) anchor in the cell membrane; meaning that these GPI-anchored proteins have no intracellular components and thus require binding partners to communicate their interactions with other proteins on cell surfaces. CNTNs are involved in various aspects of neurodevelopment and neuronal maintenance, where they can bind to partners in both -cis and -trans orientations. Among known CNTN ligands include members of the Amyloid Precursor Protein (APP) family, another well conserved group of cell surface proteins found throughout the metazoan lineage. The APP family consists of three members and follow a general architecture of two structured domains: The N-terminal E1 domain and the E2 domain, followed by the flexible transmembrane domain and the intrinsically disordered intracellular domain at the C-terminus. APP is believed to play a significant role in Alzheimer’s disease (AD) where proteolytic fragments of this protein contribute to neurodegenerative plaques. However, APP also has several neurodevelopmental functions. Previous work has focused on APP-CNTN4 complexes and their implications during the development of the accessory optic system in mice. Nevertheless, a complete and detailed portrait of all APP-CNTN interactions has remained elusive. Here, we present data regarding the structure and biochemical characteristics of APP-CNTN complexes. We have solved several APP family-CNTN structures which illustrate how these ¬-cis interactions occur between the copper binding subdomain of APP E1 and the FN-2 domain of CNTN, and we argue that the mode of these interactions is conserved throughout vertebrates. Furthermore, we have quantified these interactions and have determined their kinetics to be rapid and of weak to moderate affinity. Finally, we present data suggesting that APP family-CNTN complexes are intimately involved in the development of the olfactory sensory nervous system in zebrafish, suggesting an evolutionarily conserved function of APP family-CNTN binding in the vertebrate lineage. Taken together, we believe we have set the stage for future investigations into APP-CNTN interactions in neurodevelopment.
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Introduction -- Methods -- APP Family CNTN Interactome -- APP-CNTN Crystal Structures -- Discussion and Future Directions -- Appendix
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Ph.D. (Doctor of Philosophy)