Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Dev Cell. 2010 Mar 16;18(3):425-36. doi: 10.1016/j.devcel.2010.01.015.
Adaptor protein 4 (AP-4) is the most recently discovered and least well-characterized member of the family of heterotetrameric adaptor protein (AP) complexes that mediate sorting of transmembrane cargo in post-Golgi compartments. Herein, we report the interaction of an YKFFE sequence from the cytosolic tail of the Alzheimer's disease amyloid precursor protein (APP) with the mu4 subunit of AP-4. Biochemical and X-ray crystallographic analyses reveal that the properties of the APP sequence and the location of the binding site on mu4 are distinct from those of other signal-adaptor interactions. Disruption of the APP-AP-4 interaction decreases localization of APP to endosomes and enhances gamma-secretase-catalyzed cleavage of APP to the pathogenic amyloid-beta peptide. These findings demonstrate that APP and AP-4 engage in a distinct type of signal-adaptor interaction that mediates transport of APP from the trans-Golgi network (TGN) to endosomes, thereby reducing amyloidogenic processing of the protein.
衔接蛋白 4（AP-4）是最近发现的异四聚体衔接蛋白（AP）复合物家族中特征研究最少的成员，该复合物介导跨膜货物在高尔基后区室中的分拣。在此，我们报告了阿尔茨海默病淀粉样前体蛋白（APP）胞质尾部的 YKFFE 序列与 AP-4 的 mu4 亚基的相互作用。生化和 X 射线晶体学分析表明，APP 序列的特性和结合部位在 mu4 上的位置与其他信号衔接相互作用不同。破坏 APP-AP-4 相互作用会降低 APP 向内体的定位，并增强 γ-分泌酶催化 APP 裂解为致病性淀粉样β肽。这些发现表明，APP 和 AP-4 参与了一种独特的信号衔接相互作用，该相互作用介导了 APP 从反式高尔基体网络（TGN）到内体的运输，从而减少了蛋白质的淀粉样形成加工。
