Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139.
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065.
Cold Spring Harb Perspect Med. 2017 Dec 1;7(12):a024067. doi: 10.1101/cshperspect.a024067.
The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other components such as TMP21 may exist in a subset of specialized complexes. The presenilin complex is the founding member of a unique class of aspartyl proteases that catalyze the γ, ɛ, ζ site cleavage of the transmembrane domains of Type I membrane proteins including amyloid precursor protein (APP) and Notch. Here, we detail the structural and chemical biology of this unusual enzyme. Taken together, these studies suggest that the complex exists in several conformations, and subtle long-range (allosteric) shifts in the conformation of the complex underpin substrate access to the catalytic site and the mechanism of action for allosteric inhibitors and modulators. Understanding the mechanics of these shifts will facilitate the design of γ-secretase modulator (GSM) compounds that modulate the relative efficiency of γ, ɛ, ζ site cleavage and/or substrate specificity.
早老素蛋白是包含早老素 1 或 2、前咽缺陷蛋白 1（APH1）、尼卡斯特林和 PEN-2 的四聚体复合物的催化亚基。其他成分，如 TMP21，可能存在于一些特殊的复合物中。早老素复合物是一种独特的天冬氨酸蛋白酶家族的创始成员，它催化 I 型跨膜蛋白（包括淀粉样前体蛋白（APP）和 Notch）的跨膜结构域的 γ、ɛ、ζ 位点切割。在这里，我们详细介绍了这种不寻常酶的结构和化学生物学。综上所述，这些研究表明，该复合物存在于几种构象中，复合物构象的细微远程（变构）变化为底物进入催化位点以及变构抑制剂和调节剂的作用机制提供了支持。了解这些变化的力学机制将有助于设计 γ-分泌酶调节剂（GSM）化合物，这些化合物可以调节 γ、ɛ、ζ 位点切割的相对效率和/或底物特异性。
