Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA.
Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3802-7. doi: 10.1073/pnas.1119075109. Epub 2012 Feb 21.
Mint adaptor proteins bind to the amyloid precursor protein (APP) and regulate APP processing associated with Alzheimer's disease; however, the molecular mechanisms underlying Mint regulation in APP binding and processing remain unclear. Biochemical, biophysical, and cellular experiments now show that the Mint1 phosphotyrosine binding (PTB) domain that binds to APP is intramolecularly inhibited by the adjacent C-terminal linker region. The crystal structure of a C-terminally extended Mint1 PTB fragment reveals that the linker region forms a short α-helix that folds back onto the PTB domain and sterically hinders APP binding. This intramolecular interaction is disrupted by mutation of Tyr633 within the Mint1 autoinhibitory helix leading to enhanced APP binding and β-amyloid production. Our findings suggest that an autoinhibitory mechanism in Mint1 is important for regulating APP processing and may provide novel therapies for Alzheimer's disease.
Mint 衔接蛋白与淀粉样前体蛋白 (APP) 结合，并调节与阿尔茨海默病相关的 APP 加工；然而，Mint 调节 APP 结合和加工的分子机制尚不清楚。生化、生物物理和细胞实验表明，Mint1 磷酸酪氨酸结合（PTB）结构域与 APP 结合受到相邻 C 末端连接区的分子内抑制。C 末端延伸的 Mint1 PTB 片段的晶体结构表明，连接区形成一个短的α-螺旋，折叠回 PTB 结构域并阻碍 APP 结合。Mint1 自身抑制螺旋内 Tyr633 的突变破坏了这种分子内相互作用，导致 APP 结合和β-淀粉样蛋白产生增强。我们的发现表明，Mint1 中的自动抑制机制对于调节 APP 加工很重要，可能为阿尔茨海默病提供新的治疗方法。
