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Publication : Autoinhibition of Mint1 adaptor protein regulates amyloid precursor protein binding and processing.

First Author  Matos MF Year  2012
Journal  Proc Natl Acad Sci U S A Volume  109
Issue  10 Pages  3802-7
PubMed ID  22355143 Mgi Jnum  J:182136
Mgi Id  MGI:5314823 Doi  10.1073/pnas.1119075109
Citation  Matos MF, et al. (2012) Autoinhibition of Mint1 adaptor protein regulates amyloid precursor protein binding and processing. Proc Natl Acad Sci U S A 109(10):3802-7
abstractText  Mint adaptor proteins bind to the amyloid precursor protein (APP) and regulate APP processing associated with Alzheimer's disease; however, the molecular mechanisms underlying Mint regulation in APP binding and processing remain unclear. Biochemical, biophysical, and cellular experiments now show that the Mint1 phosphotyrosine binding (PTB) domain that binds to APP is intramolecularly inhibited by the adjacent C-terminal linker region. The crystal structure of a C-terminally extended Mint1 PTB fragment reveals that the linker region forms a short alpha-helix that folds back onto the PTB domain and sterically hinders APP binding. This intramolecular interaction is disrupted by mutation of Tyr633 within the Mint1 autoinhibitory helix leading to enhanced APP binding and beta-amyloid production. Our findings suggest that an autoinhibitory mechanism in Mint1 is important for regulating APP processing and may provide novel therapies for Alzheimer's disease.
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