4DBB: The PTB Domain of Mint1 IS Autoinhibited by a Helix in the C-terminal Linker Region

Citation:
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 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.
PDB ID: 4DBBDownload
MMDB ID: 97836
PDB Deposition Date: 2012/1/13
Updated in MMDB: 2017/06 
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Source Organism:
Similar Structures:
Biological Unit for 4DBB: monomeric; determined by author and by software (PISA)
Molecular Components in 4DBB
Label Count Molecule
Protein (1 molecule)
1
Amyloid Beta A4 Precursor Protein-binding Family a Member 1
(Gene: Apba1)
Molecule annotation
Chemicals (7 molecules)
1
1
2
2
3
2
4
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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