FUNCTION OF THE FE65/APP COMPLEX

描述(申请人提供)：FE65是一个由三个蛋白质相互作用结构域组成的适配蛋白。它包含一个WW域和两个PI域。FE65通过其羧基末端的PI结构域(PID2)与APP结合。FE65最初被描述为一种转录激活因子，在细胞核和细胞质中都可以找到。后来，它被证明结合了APP的细胞质区域，并深刻地改变了APP的处理和贩运。最近的报道表明，FE65可以定位于细胞核，并且全长APP可以作为FE65的胞内锚定。FE65 PID1可以结合转录因子CP2/LSF/LBP1，也可以结合细胞核中的组蛋白乙酰转移酶Tip60，调节转录。与Noch胞内结构域(NICD)类似，FE65被认为与APP(Gamma-CTF)的伽马裂解胞质尾部结合，并移位到与Tip60结合并激活转录的细胞核。 这一提议的中心假设是，包括APP的伽马-CTF片段和适配器FE65在内的复合体是转录调节因子。 这项建议的具体目标是： 具体目的1.鉴定涉及FE65的核大分子复合体和APP的伽马裂解胞质尾巴。 具体目的2.发现FE65/γ-CTF复合体调控转录的基因。 具体目的3.阐明调控FE65/γ-CTF复合体形成和核转位的信号。

DESCRIPTION (provided by applicant): FE65 is an adapter protein composed of three protein-protein interaction domains. It contains a WW domain and two PI domains. FE65 binds to APP through its carboxy-terminal PI domain (PID2). FE65 was initially described as a transcriptional activator, which can be found both in the nucleus and the cytoplasm. It was later shown to bind the cytoplasmic domain of APP and to profoundly alter APP processing and trafficking. Recent reports have shown that FE65 can localize to the nucleus and that full-length APP serves as a cytosolic anchor for FE65. FE65 PID1 can bind the transcription factor CP2/LSF/LBP1 and can also bind the histone acetyl transferase Tip60 in the nucleus and modulate transcription. In analogy to the notch intracellular domain (NICD), it is suggested that FE65 binds to the gamma-cleaved cytoplasmic tail of APP (gamma-CTF) and translocates to the nucleus where it binds Tip60 and activates transcription. The central hypothesis of this proposal is that a complex, including the gamma-CTF fragment of APP and the adaptor FE65, is a regulator of transcription. The specific aims of this proposal are: Specific Aim 1. To identify the nuclear macromolecular complex that involves FE65 and the gamma-cleaved cytoplasmic tail of APP. Specific Aim 2. To discover genes whose transcription is regulated by the FE65/gamma-CTF complex. Specific Aim 3. To elucidate signals that regulate the formation and nuclear translocation of the FE65/gamma-CTF complex.