Lille University, CNRS UMR8576, Lille, France.
Lille University, INSERM UMR1167, Pasteur Institute of Lille, Lille, France.
FEBS J. 2017 Oct;284(19):3218-3229. doi: 10.1111/febs.14185. Epub 2017 Aug 30.
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/BIN1 interaction as well as the molecular details of this interaction are still not fully resolved. As a consequence, how BIN1 through its interaction with Tau affects AD risk is also still not determined. To progress in this understanding, interaction of Tau with two BIN1 isoforms was investigated using Nuclear Magnetic Resonance spectroscopy. H, N spectra showed that the C-terminal SH3 domain of BIN1 isoform 1 (BIN1Iso1) is not mobile in solution but locked with the core of the protein. In contrast, the SH3 domain of BIN1 isoform 9 (BIN1Iso9) behaves as an independent mobile domain. This reveals an equilibrium between close and open conformations for the SH3 domain. Interestingly, a 334-376 peptide from the clathrin and AP-2-binding domain (CLAP) domain of BIN1Iso1, which contains a SH3-binding site, is able to compete with BIN1-SH3 intramolecular interaction. For both BIN1 isoforms, the SH3 domain can interact with Tau(210-240) sequence. Tau(210-240) peptide can indeed displace the intramolecular interaction of the BIN1-SH3 of BIN1Iso1 and form a complex with the released domain. The measured K were in agreement with a stronger affinity of Tau peptide. Both CLAP and Tau peptides occupied the same surface on the BIN1-SH3 domain, showing that their interaction is mutually exclusive. These results emphasize an additional level of complexity in the regulation of the interaction between BIN1 and Tau dependent of the BIN1 isoforms.
桥接整合因子 1（bin1）基因是阿尔茨海默病（AD）的遗传决定因素，据报道，它通过涉及 Tau 的途径来调节阿尔茨海默病的发病机制。Tau/BIN1 相互作用的功能影响以及这种相互作用的分子细节尚未完全解决。因此，BIN1 通过与 Tau 的相互作用如何影响 AD 风险也尚未确定。为了在这方面取得进展，使用核磁共振波谱研究了 Tau 与两个 BIN1 异构体的相互作用。H、N 谱表明，BIN1 异构体 1（BIN1Iso1）的 C 端 SH3 结构域在溶液中没有移动，但与蛋白质的核心锁定。相比之下，BIN1 异构体 9（BIN1Iso9）的 SH3 结构域表现为独立的可移动结构域。这揭示了 SH3 结构域的紧密和开放构象之间的平衡。有趣的是，BIN1Iso1 的网格蛋白和 AP-2 结合域（CLAP）域的 334-376 肽，包含一个 SH3 结合位点，能够与 BIN1-SH3 分子内相互作用竞争。对于两种 BIN1 异构体，SH3 结构域都可以与 Tau(210-240)序列相互作用。Tau(210-240)肽确实可以置换 BIN1Iso1 的 BIN1-SH3 的分子内相互作用，并与释放的结构域形成复合物。测量的 K 值与 Tau 肽更强的亲和力一致。CLAP 和 Tau 肽都占据了 BIN1-SH3 结构域的相同表面，表明它们的相互作用是相互排斥的。这些结果强调了 BIN1 和 Tau 之间的相互作用的调节在依赖 BIN1 异构体的情况下具有额外的复杂性。
