Intramolecular Inhibition of the Ptb Domain in the Aida1 Neuronal Scaffolding Protein

Scaffolding proteins serve key functions in signalling cascades through mediating protein-protein interactions. A prominent member of the neuronal post-synaptic density is AIDA1, which is known to bind amyloid precursor protein (APP), a contributor to Alzheimer’s Disease (AD) development. Among the isoforms of AIDA1, AIDA1b is the largest and is unique in that its phosphotyrosine binding (PTB) domain is autoinhibited; thus, it cannot bind APP until this inhibition is relieved. This thesis presents structural and functional studies on AIDA1b. Fluorescence anisotropy and biolayer interferometry assays confirmed that the deletion of Exon 14 relieves the autoinhibition of the PTB domain, allowing AIDA1b to bind APP. However, Exon 14’s removal does not significantly impact the thermostability of AIDA1b. Moreover, Exon 14 contributes an alpha helical structural, with 3D bead models exhibiting potential domain reorganization upon Exon 14’s removal. The predicted structure of Exon 14 is an amphipathic alpha helix that presumably contacts the PTB domain in cooperation with other intervening sequences. Overall, AIDA1b can play a potential role in AD pathogenesis, with potential for contribution to novel therapeutic development.