Open-closed motion of Mint2 regulates APP metabolism.
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.
State Key Laboratory of Medicinal Chemical Biology,  Nankai University, 94 Weijin Road, Tianjin 300071,  China.
Xingqiao
X
Xie
Xiaojie
X
Yan
Zheng
Z
Wang
Hao
H
Zhou
Wentao
W
Diao
Weihong
W
Zhou
Jiafu
J
Long
Yuequan
Y
Shen
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C491635:Apba2 protein, mouse; D002352:Carrier Proteins; D008024:Ligands; D009419:Nerve Tissue Proteins