Mint2以“打开—闭合”构象变化来调节APP的代谢
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摘要
阿尔兹海默病(Alzheimer's disease, AD)是一种神经退化性失调,困扰着全球数百万的老龄人。本文基于晶体结构及后续的生化和功能手段研究了在AD发病机制中起着重要作用的两个蛋白Mint2和amyloid-β protein precursor (APP)。
Aβ的沉积是AD病的一个重要标志,它的产生来自APP有序分解。APP的转运和代谢的调节取决于结合到APP胞内末端的蛋白,这其中就包括Mint蛋白家族。Mint蛋白家族,是一个含多个蛋白-蛋白相互作用结构域的支架蛋白家族。Mint蛋白家族包括一个变化的氮端区域和一个保守性很高的碳端区域,其碳端区域包含一个重要的phosphotyrosine-binding (PTB)结构域,一对串联排列的PDZ结构域和最末端的C端(之后简称PPC)。通过这些结构域,Mints介导组装成功能各异的蛋白复合体,最引入注目的是能够调节APP的代谢过程和参与amyloid-β多肽(Aβ)的生成。Mint蛋白家族的PTB结构域能结合APP的YENPTY模序。但是APP动态结合Mint2的分子机制还不清楚。
本文报道了结合及没有结合APP多肽的Mint2-PPC的两个晶体结构,其分辨率分别为3.3A和2.7A。这些结构表明没有结合APP多肽的Mint2-PPC以“闭合”的构象存在,在这个状态中ARM结构域盖住了PTB结构域的APP多肽结合口袋。而与之完全相反的是,结合APP多肽的Mint2-PPC以“打开”的构象存在,此时ARM结构域彻底从结合多肽处旋转开来。体内和体外实验证明了控制Mint2“打开—闭合”构象变化的不同突变体动态调节APP代谢。我们的实验结果揭示了PTB结构域一种崭新的“打开—闭合”构象变化动态地结合它的多肽底物的机制。此外,这种构象变化可能代表Mint蛋白家族调节APP蛋白家族的一种普遍模式,为AD疾病的治疗提供有用的信息。
Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions of elderly people worldwide. Based on the crystal structures and detailed biochemical and functional strategies, we studied the scafolding protein Mint2-mediated amyloid-p protein precursor (APP) metabolism in the pathogenesis of AD.
The deposition of neurotoxic Aβ is a major hallmark of AD, The production of Aβ is accomplished by the sequential cleavage of the APP. The regulation of the trafficking and processing of APP depends on the cytosolic proteins that bind to the intracellular tail of APP, which include proteins from the Mint family.The Mint protein family are multidomain scafolding proteins. The Mint proteins (Mints) have a variable N-terminal region and a highly conserved C-terminal region that contains a central phosphotyrosine-binding (PTB) domain, a tandem PDZ domain and the very end of C-terminus (hereafter referred to as PPC). Through these domains, Mints mediate the assembly of functional protein complexes. Strikingly, they can modulate processing of APP and production of amyloid-β(Aβ). The PTB domains found in the Mint family are capable of interacting with the YENPTY motif of APP. However, the molecular mechanism of APP dynamically binding to Mint2remains elusive.
Here, we report the structures of APP peptide-free and APP peptide-bound C-terminal Mint2mutants (Min2-PPC) at resolutions of2.7and3.3A, respectively. Our structures reveal that APP peptide-free Mint2-PPC exists in a closed state in which the ARM domain blocks the peptide-binding groove of the PTB domain. In sharp contrast, APP peptide-bound Mint2-PPC exists in an open state in which the ARM domain drastically swings away from the bound peptide. Mutants that control the open-closed motion of Mint2dynamically regulated APP metabolism both in vitro and in vivo. Our results uncover a novel open-closed mechanism of the PTB domain dynamically binding to its peptide substrate. Moreover, such a conformational switch may represent a general regulation mode of APP family members by Mint proteins, providing useful information for the treatment of AD.
Aβ的沉积是AD病的一个重要标志,它的产生来自APP有序分解。APP的转运和代谢的调节取决于结合到APP胞内末端的蛋白,这其中就包括Mint蛋白家族。Mint蛋白家族,是一个含多个蛋白-蛋白相互作用结构域的支架蛋白家族。Mint蛋白家族包括一个变化的氮端区域和一个保守性很高的碳端区域,其碳端区域包含一个重要的phosphotyrosine-binding (PTB)结构域,一对串联排列的PDZ结构域和最末端的C端(之后简称PPC)。通过这些结构域,Mints介导组装成功能各异的蛋白复合体,最引入注目的是能够调节APP的代谢过程和参与amyloid-β多肽(Aβ)的生成。Mint蛋白家族的PTB结构域能结合APP的YENPTY模序。但是APP动态结合Mint2的分子机制还不清楚。
本文报道了结合及没有结合APP多肽的Mint2-PPC的两个晶体结构,其分辨率分别为3.3A和2.7A。这些结构表明没有结合APP多肽的Mint2-PPC以“闭合”的构象存在,在这个状态中ARM结构域盖住了PTB结构域的APP多肽结合口袋。而与之完全相反的是,结合APP多肽的Mint2-PPC以“打开”的构象存在,此时ARM结构域彻底从结合多肽处旋转开来。体内和体外实验证明了控制Mint2“打开—闭合”构象变化的不同突变体动态调节APP代谢。我们的实验结果揭示了PTB结构域一种崭新的“打开—闭合”构象变化动态地结合它的多肽底物的机制。此外,这种构象变化可能代表Mint蛋白家族调节APP蛋白家族的一种普遍模式,为AD疾病的治疗提供有用的信息。
Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions of elderly people worldwide. Based on the crystal structures and detailed biochemical and functional strategies, we studied the scafolding protein Mint2-mediated amyloid-p protein precursor (APP) metabolism in the pathogenesis of AD.
The deposition of neurotoxic Aβ is a major hallmark of AD, The production of Aβ is accomplished by the sequential cleavage of the APP. The regulation of the trafficking and processing of APP depends on the cytosolic proteins that bind to the intracellular tail of APP, which include proteins from the Mint family.The Mint protein family are multidomain scafolding proteins. The Mint proteins (Mints) have a variable N-terminal region and a highly conserved C-terminal region that contains a central phosphotyrosine-binding (PTB) domain, a tandem PDZ domain and the very end of C-terminus (hereafter referred to as PPC). Through these domains, Mints mediate the assembly of functional protein complexes. Strikingly, they can modulate processing of APP and production of amyloid-β(Aβ). The PTB domains found in the Mint family are capable of interacting with the YENPTY motif of APP. However, the molecular mechanism of APP dynamically binding to Mint2remains elusive.
Here, we report the structures of APP peptide-free and APP peptide-bound C-terminal Mint2mutants (Min2-PPC) at resolutions of2.7and3.3A, respectively. Our structures reveal that APP peptide-free Mint2-PPC exists in a closed state in which the ARM domain blocks the peptide-binding groove of the PTB domain. In sharp contrast, APP peptide-bound Mint2-PPC exists in an open state in which the ARM domain drastically swings away from the bound peptide. Mutants that control the open-closed motion of Mint2dynamically regulated APP metabolism both in vitro and in vivo. Our results uncover a novel open-closed mechanism of the PTB domain dynamically binding to its peptide substrate. Moreover, such a conformational switch may represent a general regulation mode of APP family members by Mint proteins, providing useful information for the treatment of AD.
引文
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