Open–closed motion of Mint2 regulates APP metabolism
| Autor: | Hao Zhou, Weihong Zhou, Zheng Wang, Wentao Diao, Xiaojie Yan, Yuequan Shen, Xingqiao Xie, Jiafu Long |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Protein Conformation Mutant Mice Transgenic Nerve Tissue Proteins Plasma protein binding Biology Ligands medicine.disease_cause Cell Line Amyloid beta-Protein Precursor Mice Protein structure Alzheimer Disease mental disorders Genetics medicine Animals Humans Protein Interaction Domains and Motifs Protein precursor Molecular Biology Mutation Amyloid beta-Peptides Adaptor Signaling Protein Signal transducing adaptor protein Cell Biology General Medicine Cell biology Disease Models Animal Biochemistry Carrier Proteins Phosphotyrosine-binding domain |
| Zdroj: | Journal of Molecular Cell Biology. 5:48-56 |
| ISSN: | 1759-4685 1674-2788 |
| DOI: | 10.1093/jmcb/mjs033 |
| Popis: | The amyloid-β protein precursor (APP) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Knock-out and transgenic mouse studies of the adaptor protein Mint2 have revealed that it is a major player in regulating APP metabolism physiologically through the binding of its phosphotyrosine-binding (PTB) domain to the intracellular domain of APP. However, the molecular mechanism of APP dynamically binding to Mint2 remains elusive. Here, we report the structures of APP peptide-free and APP peptide-bound C-terminal Mint2 mutants at resolutions of 2.7 and 3.3 Å, respectively. Our structures reveal that APP peptide-free Mint2 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 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 Mint2 dynamically 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. |
| Databáze: | OpenAIRE |
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