The regions of the Fe65 protein homologous to the PID/PTB domain of Shc bind the intracellular domain of the Alzheimer's amyloid precursor

Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.
Journal of Biological Chemistry (Impact Factor: 4.57). 01/1996; 270(52):30853-6. DOI: 10.1074/jbc.270.52.30853
Source: PubMed


Fe65 is a protein mainly expressed in several districts of the mammalian nervous system. The search of protein sequence data banks revealed that Fe65 contains two phosphotyrosine interaction (PID) or phosphotyrosine binding (PTB) domains, previously identified in the Shc adaptor molecule. The two putative PID/PTB domains of Fe65 were used to construct glutathione S-transferase-Fe65 fusion proteins. Co-precipitation experiments demonstrated that the Fe65 PID/PTB domains interacted with several proteins of apparent molecular mass 135, 115, 105, and 51 kDa. The region of Fe65 containing the PID/PTB domains was used as a bait to screen a human brain cDNA library in yeast by the two-hybrid system. Three different cDNA clones were isolated, two of which contain overlapping segments of the cDNA encoding the COOH terminus of the Alzheimer's beta-amyloid-precursor protein (APP), that represents the short intracellular domain of this membrane protein. The third clone contains a cDNA fragment coding for the COOH terminus of the human counterpart of a mouse beta-amyloid-like precursor protein. The alignment of the three APP encoding cDNA fragments found in the screening suggests that the region of APP involved in the binding is centered on the NPTY sequence, which is analogous to that present in the intracellular domains of the growth factor receptors interacting with the PID/PTB domain of Shc.

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    • "[17] "
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    ABSTRACT: This special issue is devoted to revisit the “amyloid cascade hypothesis” (ACH) in the pathogenesis of sporadic Alzheimer’s disease (AD). Since the identification 20 years ago of the first APP mutation [1] the ACH gained enormous importance based on genetic and biochemical evidence. However the outcome of recent clinical trials aimed at reducing extracellular Aβ levels suggests that such strategy may not have the expected impact on AD progression because the role of Aβ is more complex than that of the lone driver of AD. Some of the reasons proposed for the failure may be the initiation of the trials in demented patients with serious brain damage, and unforeseen serious design flaws in the studies. These results led us to ask whether Aβ plays an active protective role in brain aging. It is also clear that regardless of whether Aβ is protective or toxic, trials focused on modulating the Aβ response will remain a major interest in AD therapeutic research.
    2012 edited by Laura Morelli, George Perry, Fabrizio Tagliavini, 08/2012; Hindawi Publishing Company., ISBN: 2090-8024
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    • "These authors showed that the proteolytic fragment AICD of APP could rescue Ca 2+ deficits present in APP -/-cells. Recent data suggest that AICD forms complex with other transcription factors (CP2/LS/LBP1) (Minopoli et al. 2001; Fiore et al. 1995) and this transcription factor complex may regulate the expression of neuronal Ca 2+ -signaling proteins such as ER calcium ATPase which is responsible for transporting Ca 2+ from cytosol to the lumen of the ER (Leissring et al. 2002). Another hypothesis is that Ab peptide generated by csecretase-mediated processing of APP may associate to form Ca 2+ -permeable channels in the plasma membrane of neurons causing Ca 2+ influx from outside the cells into cytoplasm (Arispe et al. 1993). "
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    ABSTRACT: J. Neurochem. (2012) 122, 487–500. Genetic deletion or mutations of presenilin genes (PS1/PS2) cause familial Alzheimer’s disease and calcium (Ca2+) signaling abnormalities. PS1/PS2 act as endoplasmic reticulum (ER) Ca2+ leak channels that facilitate passive Ca2+ leak across ER membrane. Studies with PS1/PS2 double knockout (PS1/PS2-DKO) mouse embryonic fibroblasts showed that PS1/PS2 were responsible for 80% of passive Ca2+ leak from the lumen of endoplasmic reticulum to cytosol. Transient transfection of the wild type PS1 expression construct increased cytoplasmic Ca2+ as a result of Ca2+ leak across ER membrane whereas the FADPS1 (PS1-M146V) mutation construct alone or in combination with the wild type PS1 expression construct abrogated Ca2+ leak in SK-N-SH cells. Inhibition of basal c-jun-NH2-terminal kinase (JNK) activity by JNK inhibitor SP600125 repressed PS1 transcription and PS1 protein expression by augmenting p53 protein level in SK-N-SH cells (Lee and Das 2008). In this report we also showed that repression of PS1 transcription by JNK inhibitor SP600125 inhibited passive Ca2+ leak across ER membrane which could be rescued by expressing PS1 wild type and not by expressing FADPS1 (PS1-M146V) under a SP600125 non-responsive promoter. Treatment of SK-N-SH cells with SP600125 also triggered InsP3R-mediated Ca2+ release from the ER by addition of 500 nM bradykinin, an agonist of InsP3 receptor (InsP3R1) without changing the expression of InsP3R1. This data confirms that SP600125 increases the Ca2+ store in the ER by inhibiting PS1-mediated Ca2+ leak across ER membrane. p53, ZNF237 and Chromodomain helicase DNA-binding protein 3 which are repressors of PS1 transcription, also reduced Ca2+ leak across ER membrane in SK-N-SH cells but γ-secretase inhibitor or dominant negative γ-secretase–specific PS1 mutant (PS1-D257A) had no significant effect. Therefore, p53, ZNF237, and Chromodomain helicase DNA-binding protein 3 inhibit the function ER Ca2+ leak channels to regulate both ER and cytoplasmic Ca2+ levels and may potentially control Ca2+-signaling function of PS1.
    Journal of Neurochemistry 05/2012; 122(3):487-500. DOI:10.1111/j.1471-4159.2012.07794.x · 4.28 Impact Factor
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    • "Protein Domain involved Putative functions of the interaction References Amyloid precursor protein (APP) PTB2 Regulation of Aβ secretion, nuclear signaling, and cytoskeleton regulation [17] "
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    ABSTRACT: Since its proposal in 1994, the amyloid cascade hypothesis has prevailed as the mainstream research subject on the molecular mechanisms leading to the Alzheimer's disease (AD). Most of the field had been historically based on the role of the different forms of aggregation of β-amyloid peptide (Aβ). However, a soluble intracellular fragment termed amyloid precursor protein (APP) intracellular domain (AICD) is produced in conjunction with Aβ fragments. This peptide had been shown to be highly toxic in both culture neurons and transgenic mice models. With the advent of this new toxic fragment, the centerpiece for the ethiology of the disease may be changed. This paper discusses the potential role of multiprotein complexes between the AICD and its adapter protein Fe65 and how this could be a potentially important new agent in the neurodegeneration observed in the AD.
    International Journal of Alzheimer's Disease 02/2012; 2012(11):353145. DOI:10.1155/2012/353145
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