Amyloid precursor protein associates independently and collaboratively with PTB and PDZ domains of mint on vesicles and at cell membrane

M. Okamoto et al., Amyloid precursor protein associates independently and collaboratively with PTB and PDZ domains of mint on vesicles and at cell membrane, NEUROSCIENC, 104(3), 2001, pp. 653-665
Citations number
Categorie Soggetti
Neurosciences & Behavoir
Journal title
ISSN journal
0306-4522 → ACNP
Year of publication
653 - 665
SICI code
The mint family consists of evolutionarily conserved adapter proteins from Caenorhabditis elegans to mammalian neurons. Three mammalian isoforms. mint 1, 2, and 3, are extensively diverted in their N-terminal halves and, in s triking contrast, are highly homologous to each other in their C-terminal h alves containing phospho tyrosine-binding (PTB) and PSD-95/DLG-A/ZO-1 (PDZ) domains that work as protein-protein interaction modules. Biochemical and genetic analyses revealed that mint 1 and LIN-10. a homolog in C. elegans, comprise macromolecular complexes in the presynaptic and postsynaptic termi nals. thereby bringing synaptic vesicles to the exocytotic transmitter rele ase site and localizing receptors and ion channels in the specific membrane domains, Amyloid precursor protein is one of the targets of the PTB domain of mint and this interaction modulates its proteolytic procedures ending u p with amyloid beta peptide production, but its molecular mechanism is uncl ear. We show; by an in situ hybridization technique that mint3, a ubiquitou s isoform, is expressed both in polar cells like neurons, and in non-polar cells, such as glia and ependymal cells, in the mouse brain. In addition, a considerable amount of a human homolog mint3 ( approximate to 70 kDa) was expressed in a human epithelial cell line. Subcellularly. mint3 is specific ally enriched in vesicles in the cytoplasm. cell membrane, and Golgi comple x as reserves. A series of deletions or site-directed mutations revealed th at mint3 double recognizes an amyloid precursor protein-containing macromol ecular complex via the PTB and PDZb domains independently and cooperatively . not only in the cytoplasmic transporting vesicles but even after amyloid precursor protein was targeted and/or inserted to the specific: cell membra ne domains. From these results we suggest that mint3 links amyloid precursor protein to other components. thereby regulating its transport. endocytosis, and metab olism. Abnormal metabolism of amyloid precursor protein causes an early-ons et type of Alzheimer's disease bur its molecular mechanism is incompletely understood. The present findings give morphological evidence and a molecula r framework of how mint interacts with amyloid precursor protein and modifi es its processing on the secretor); pathway. (C) 2001 IBRO. Published by El sevier Science Ltd. All rights reserved.