Journal
BIOCHEMICAL JOURNAL
Volume 436, Issue -, Pages 631-639Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20110145
Keywords
Alzheimer's disease; amyloid-beta peptide (A beta); amyloid precursor protein (APP); amyloid precursor protein intracellular domain (AICD); CED-6; engulfment adaptor protein 1 (GULP1)
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Funding
- Research Grant Council Hong Kong [CUHK 469610]
- Chinese University of Hong Kong (CUHK) [2030428]
- United College endowment fund research grant
- Wellcome Trust
- UK Medical Research Council
- MRC [G0501573] Funding Source: UKRI
- Medical Research Council [G0501573] Funding Source: researchfish
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Altered production of A beta (amyloid-beta peptide), derived from the proteolytic cleavage of APP (amyloid precursor protein), is believed to be central to the pathogenesis of AD (Alzheimer's disease). Accumulating evidence reveals that APPc (APP C-terminal domain)-interacting proteins can influence APP processing. There is also evidence to suggest that APPc-interacting proteins work co-operatively and competitively to maintain normal APP functions and processing. Hence, identification of the full complement of APPc-interacting proteins is an important step for improving our understanding of APP processing. Using the yeast two-hybrid system, in the present study we identified GULP1 (engulfment adaptor protein 1) as a novel APPc-interacting protein. We found that the GULP1-APP interaction is mediated by the NPTY motif of APP and the GULP1 PTB (phosphotyrosine-binding) domain. Confocal microscopy revealed that a proportion of APP and GULP1 co-localized in neurons. In an APP-GAL4 reporter assay, we demonstrated that GULP1 altered the processing of APP. Moreover, overexpression of GULP1 enhanced the generation of APP CTEs (C-terminal fragments) and A beta, whereas knockdown of GULP1 suppressed APP CTFs and A beta production. The results of the present study reveal that GULP1 is a novel APP/APPc-interacting protein that influences APP processing and A beta production.
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