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Open-closed motion of Mint2 regulates APP metabolism.

Authors: Xie, Xingqiao  Yan, Xiaojie  Wang, Zheng  Zhou, Hao  Diao, Wentao  Zhou, Weihong  Long, Jiafu  Shen, Yuequan 
Citation: Xie X, etal., J Mol Cell Biol. 2013 Feb;5(1):48-56. doi: 10.1093/jmcb/mjs033. Epub 2012 Jun 21.
Pubmed: (View Article at PubMed) PMID:22730553
DOI: Full-text: DOI:10.1093/jmcb/mjs033

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.

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RGD ID: 14995319
Created: 2019-10-19
Species: All species
Last Modified: 2019-10-19
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.