Journal
NEUROSCIENCE
Volume 104, Issue 3, Pages 653-665Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0306-4522(01)00124-5
Keywords
Alzheimer's disease; amyloid precursor protein; mint; PDZ domain; PTB domain; vesicle trafficking
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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 striking contrast, are highly homologous to each other in their C-terminal halves 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 terminals. thereby bringing synaptic vesicles to the exocytotic transmitter release 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 up with amyloid beta peptide production, but its molecular mechanism is unclear. We show; by an in situ hybridization technique that mint3, a ubiquitous 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 specifically enriched in vesicles in the cytoplasm. cell membrane, and Golgi complex as reserves. A series of deletions or site-directed mutations revealed that mint3 double recognizes an amyloid precursor protein-containing macromolecular 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 membrane domains. From these results we suggest that mint3 links amyloid precursor protein to other components. thereby regulating its transport. endocytosis, and metabolism. Abnormal metabolism of amyloid precursor protein causes an early-onset type of Alzheimer's disease bur its molecular mechanism is incompletely understood. The present findings give morphological evidence and a molecular framework of how mint interacts with amyloid precursor protein and modifies its processing on the secretor); pathway. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.
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