title: Autoinhibition of Mint1 adaptor protein regulates amyloid precursor protein binding and processing.
abstract: 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 α-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 β-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.
authors.affiliation: Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Matos
authors.forename: Yibin
authors.initials: Y
authors.lastname: Xu
authors.forename: Irina
authors.initials: I
authors.lastname: Dulubova
authors.forename: Zbyszek
authors.initials: Z
authors.lastname: Otwinowski
authors.forename: John M
authors.initials: JM
authors.lastname: Richardson
authors.forename: Diana R
authors.initials: DR
authors.lastname: Tomchick
authors.forename: Josep
authors.initials: J
authors.lastname: Rizo
authors.forename: Angela
authors.initials: A
authors.lastname: Ho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D001671:Biochemistry / Q000379:methods; D001703:Biophysics / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D004252:DNA Mutational Analysis; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008968:Molecular Conformation; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014443:Tyrosine / Q000737:chemistry
chemical_list: C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D014443:Tyrosine