Regulation of the interaction between the neuronal BIN 1 isoform 1 and Tau proteins – role of the SH 3 domain

Bridging integrator 1 ( bin1 ) gene is a genetic determinant of Alzheimer's disease (AD) and has been reported to modulate Alzheimer's pathogenesis through pathway(s) involving Tau. The functional impact of Tau/ BIN 1 interaction as well as the molecular details of this interaction are still not fully resolved. As a consequence, how BIN 1 through its interaction with Tau affects AD risk is also still not determined. To progress in this understanding, interaction of Tau with two BIN 1 isoforms was investigated using Nuclear Magnetic Resonance spectroscopy. 1 H, 15 N spectra showed that the C‐terminal SH 3 domain of BIN 1 isoform 1 ( BIN 1Iso1) is not mobile in solution but locked with the core of the protein. In contrast, the SH 3 domain of BIN 1 isoform 9 ( BIN 1Iso9) behaves as an independent mobile domain. This reveals an equilibrium between close and open conformations for the SH 3 domain. Interestingly, a 334–376 peptide from the clathrin and AP‐2‐binding domain (CLAP) domain of BIN 1Iso1, which contains a SH 3‐binding site, is able to compete with BIN 1‐ SH 3 intramolecular interaction. For both BIN 1 isoforms, the SH 3 domain can interact with Tau(210–240) sequence. Tau(210–240) peptide can indeed displace the intramolecular interaction of the BIN 1‐ SH 3 of BIN 1Iso1 and form a complex with the released domain. The measured K d were in agreement with a stronger affinity of Tau peptide. Both CLAP and Tau peptides occupied the same surface on the BIN 1‐ SH 3 domain, showing that their interaction is mutually exclusive. These results emphasize an additional level of complexity in the regulation of the interaction between BIN 1 and Tau dependent of the BIN 1 isoforms.