Lasorsa Alessia, Malki Idir, Cantrelle François-Xavier, Merzougui Hamida, Boll Emmanuelle, Lambert Jean-Charles, Landrieu Isabelle
CNRS UMR8576, Lille University, Lille, France.
INSERM UMR1167, Pasteur Institute Lille, Lille University, Lille, France.
Front Mol Neurosci. 2018 Nov 14;11:421. doi: 10.3389/fnmol.2018.00421. eCollection 2018.
Bridging integrator-1 () gene is associated with an increased risk to develop Alzheimer's disease, a tauopathy characterized by intra-neuronal accumulation of phosphorylated Tau protein as paired helical filaments. Direct interaction of BIN1 and Tau proteins was demonstrated to be mediated through BIN1 SH3 C-terminal domain and Tau (210-240) peptide within Tau proline-rich domain. We previously showed that BIN1 SH3 interaction with Tau is decreased by phosphorylation within Tau proline-rich domain, of at least T231. In addition, the BIN1/Tau interaction is characterized by a dynamic equilibrium between a closed and open conformations of BIN1 isoform 1, involving an intramolecular interaction with its C-terminal BIN1 SH3 domain. However, the role of the BIN1/Tau interaction, and its potential dysregulation in Alzheimer's disease, is not yet fully understood. Here we showed that within Tau (210-240) peptide, among the two proline-rich motifs potentially recognized by SH3 domains, only motif PTPPTR is bound by BIN1 SH3. A structural model of the complex between BIN1 SH3 and Tau peptide (213-229), based on nuclear magnetic resonance spectroscopy data, revealed the molecular detail of the interaction. P216 and P219 within the proline-rich motif were in direct contact with the aromatic F588 and W562 of the BIN1 SH3 domain. The contact surface is extended through electrostatic interactions between the positively charged R221 and K224 residues of Tau peptide and those negatively charged of BIN1 SH3, corresponding to E556 and E557. We next investigated the impact of multiple Tau phosphorylations within Tau (210-240) on its interaction with BIN1 isoform 1. Tau (210-240) phosphorylated at four different sites (T212, T217, T231, and S235), contrary to unphosphorylated Tau, was unable to compete with the intramolecular interaction of BIN1 SH3 domain with its CLAP domain. In accordance, the affinity of BIN1 SH3 for phosphorylated Tau (210-240) peptide was reduced, with a five-fold increase in the dissociation constant, from a Kd of 44 to 256 μM. This study highlights the complexity of the regulation of BIN1 isoform 1 with Tau. As abnormal phosphorylation of Tau is linked to the pathology development, this regulation by phosphorylation might have important functional consequences.
衔接整合蛋白-1（BIN1）基因与患阿尔茨海默病的风险增加有关，阿尔茨海默病是一种tau蛋白病，其特征是神经元内磷酸化Tau蛋白以双螺旋丝的形式积累。已证明BIN1与Tau蛋白的直接相互作用是通过BIN1 SH3 C末端结构域和Tau富含脯氨酸结构域内的Tau（210 - 240）肽介导的。我们之前表明，至少在T231处，Tau富含脯氨酸结构域内的磷酸化会降低BIN1 SH3与Tau的相互作用。此外，BIN1/Tau相互作用的特征是BIN1亚型1的封闭构象和开放构象之间的动态平衡，这涉及与其C末端BIN1 SH3结构域的分子内相互作用。然而，BIN1/Tau相互作用的作用及其在阿尔茨海默病中的潜在失调尚未完全了解。在这里，我们表明在Tau（210 - 240）肽中，在可能被SH3结构域识别的两个富含脯氨酸的基序中，只有基序PTPPTR与BIN1 SH3结合。基于核磁共振光谱数据的BIN1 SH3与Tau肽（213 - 229）之间复合物的结构模型揭示了相互作用的分子细节。富含脯氨酸基序内的P216和P219与BIN1 SH3结构域的芳香族F588和W562直接接触。通过Tau肽带正电荷的R221和K224残基与BIN1 SH3带负电荷的残基（对应于E556和E557）之间的静电相互作用，接触表面得以扩展。接下来，我们研究了Tau（210 - 240）内多个Tau磷酸化对其与BIN1亚型1相互作用的影响。与未磷酸化的Tau相反，在四个不同位点（T212、T217、T231和S235）磷酸化的Tau（210 - 240）无法与BIN1 SH3结构域与其CLAP结构域的分子内相互作用竞争。相应地，BIN1 SH3对磷酸化Tau（210 - 240）肽的亲和力降低，解离常数增加了五倍，从44 μM增加到256 μM。这项研究突出了BIN1亚型1与Tau调节的复杂性。由于Tau的异常磷酸化与病理发展有关，这种磷酸化调节可能具有重要的功能后果。
