Open-closed Motion Of Mint2Regulates APP Metabolism

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.