3SV1

Crystal structure of APP peptide bound rat Mint2 PARM

Summary for 3SV1

• Entry DOI: 10.2210/pdb3sv1/pdb
• Descriptor: Amyloid beta A4 precursor protein-binding family A member 2, Amyloid beta A4 protein (3 entities in total)
• Functional Keywords: app binding, protein binding
• Biological source: Rattus norvegicus (rat); More
• Cellular location: Membrane; Single-pass type I membrane protein: P05067
• Total number of polymer chains: 6
• Total formula weight: 69164.97

Authors

Shen, Y.,Long, J.,Yan, X.,Xie, X. (deposition date: 2011-07-12, release date: 2012-07-11, Last modification date: 2023-11-01)

Primary citation

Xie, X.,Yan, X.,Wang, Z.,Zhou, H.,Diao, W.,Zhou, W.,Long, J.,Shen, Y.
Open-closed motion of Mint2 regulates APP metabolism
J Mol Cell Biol, 5:48-56, 2013

PubMed Abstract: 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.

PubMed: 22730553
DOI: 10.1093/jmcb/mjs033

Experimental method

X-RAY DIFFRACTION (3.3 Å)