4DBB

The PTB domain of Mint1 is autoinhibited by a helix in the C-terminal linker region

Summary for 4DBB

• Entry DOI: 10.2210/pdb4dbb/pdb
• Descriptor: Amyloid beta A4 precursor protein-binding family A member 1, CHLORIDE ION, ACETIC ACID, ... (6 entities in total)
• Functional Keywords: x11s/mints, ptb domain, chimera protein, protein transport
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cytoplasm . Isoform 2: Golgi apparatus : O35430
• Total number of polymer chains: 1
• Total formula weight: 18868.80

Authors

Tomchick, D.R.,Rizo, J.,Ho, A.,Xu, Y. (deposition date: 2012-01-13, release date: 2012-03-07, Last modification date: 2024-02-28)

Primary citation

Matos, M.F.,Xu, Y.,Dulubova, I.,Otwinowski, Z.,Richardson, J.M.,Tomchick, D.R.,Rizo, J.,Ho, A.
Autoinhibition of Mint1 adaptor protein regulates amyloid precursor protein binding and processing.
Proc.Natl.Acad.Sci.USA, 109:3802-3807, 2012

PubMed 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.

PubMed: 22355143
DOI: 10.1073/pnas.1119075109

Experimental method

X-RAY DIFFRACTION (1.901 Å)