title: GULP1 is a novel APP-interacting protein that alters APP processing.
abstract: Altered production of Aβ (amyloid-β 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 CTFs (C-terminal fragments) and Aβ, whereas knockdown of GULP1 suppressed APP CTFs and Aβ production. The results of the present study reveal that GULP1 is a novel APP/APPc-interacting protein that influences APP processing and Aβ production.
authors.affiliation: Biochemistry Programme, School of Life Sciences, the Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hao
authors.forename: Candy Yan
authors.initials: CY
authors.lastname: Hao
authors.forename: Michael S
authors.initials: MS
authors.lastname: Perkinton
authors.forename: William Wai-Lun
authors.initials: WW
authors.lastname: Chan
authors.forename: Ho Yin Edwin
authors.initials: HY
authors.lastname: Chan
authors.forename: Christopher C J
authors.initials: CC
authors.lastname: Miller
authors.forename: Kwok-Fai
authors.initials: KF
authors.lastname: Lau
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D009474:Neurons / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020798:Two-Hybrid System Techniques
chemical_list: C545487:APP protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C454119:GULP1 protein, human