Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Biochemistry. 2010 Apr 6;49(13):2796-804. doi: 10.1021/bi901388t.
Gamma-secretase is a widely expressed multisubunit enzyme complex which is involved in the pathogenesis of Alzheimer disease and hematopoietic malignancies through its aberrant processing of the amyloid precursor protein (APP) and Notch1, respectively. While gamma-secretase has been extensively studied, there is a dearth of information surrounding the activity, composition, and function of gamma-secretase expressed in distinct cellular populations. Here we show that endogenous gamma-secretase complexes of hematopoietic origin are distinct from epithelial derived gamma-secretase complexes. Hematopoietic gamma-secretase has reduced activity for APP and Notch1 processing compared to epithelial gamma-secretase. Characterization of the active complexes with small molecule affinity probes reveals that hematopoietic gamma-secretase has an atypical subunit composition with significantly altered subunit stoichiometry. Furthermore, we demonstrate that these discrete complexes exhibit cell-line specific substrate selectivity suggesting a possible mechanism of substrate regulation. These data underscore the need for studying endogenous gamma-secretase to fully understand of the biology of gamma-secretase and its complexity as a molecular target for the development of disease therapeutics.
γ-分泌酶是一种广泛表达的多亚基酶复合物，通过其对淀粉样前体蛋白（APP）和 Notch1 的异常加工，分别参与阿尔茨海默病和造血恶性肿瘤的发病机制。虽然 γ-分泌酶已经被广泛研究，但对于在不同细胞群中表达的 γ-分泌酶的活性、组成和功能的信息却很少。在这里，我们表明造血来源的内源性 γ-分泌酶复合物与上皮衍生的 γ-分泌酶复合物不同。与上皮 γ-分泌酶相比，造血 γ-分泌酶对 APP 和 Notch1 加工的活性降低。用小分子亲和探针对活性复合物进行表征表明，造血 γ-分泌酶具有非典型的亚基组成，亚基比例发生了显著改变。此外，我们证明这些离散的复合物表现出细胞系特异性的底物选择性，提示存在一种可能的底物调节机制。这些数据强调了研究内源性 γ-分泌酶的必要性，以充分了解 γ-分泌酶的生物学及其作为疾病治疗药物开发的分子靶标的复杂性。
