| Co-Investigator(Kenkyū-buntansha) |
NISHIMURA Hiroyuki Hyogo College of Medicine, Fifth Department of Internal Medicine, Research Associate, 医学部, 助手 (20248131)
MATSUYAMA Tomohiro Hyogo College of Medicine, Fifth Department of Internal Medicine, Assistant Professor, 医学部, 講師 (10219529)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1999: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Research Abstract |
The mint family is evolutionarily conserved adapter proteins from C.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 PTB and 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 β peptide production, but its molecular mechanism is unclear. We show by an in situ hybridization technique that mint3, a ubiquitous isoform, is expressed
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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 (【approximately equal】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. These results 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 but its molecular mechanism is incompletely understood. The present findings give morphological evidence and a molecular framework how mint interacts with amyloid precursor protein and modifies its processing on the secretory pathway. Less
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