Leibniz Institut für Altersforschung-Fritz Lipmann Institut, 07743 Jena, Germany.
Traffic. 2010 Feb;11(2):250-8. doi: 10.1111/j.1600-0854.2009.01014.x. Epub 2009 Nov 5.
gamma-Secretase is critically involved in the Notch pathway and in Alzheimer's disease. The four subunits of gamma-secretase assemble in the endoplasmic reticulum (ER) and unassembled subunits are retained/retrieved to the ER by specific signals. We here describe a novel ER-retention/retrieval signal in the transmembrane domain (TMD) 4 of presenilin 1, a subunit of gamma-secretase. TMD4 also is essential for complex formation, conferring a dual role for this domain. Likewise, TMD1 of Pen2 is bifunctional as well. It carries an ER-retention/retrieval signal and is important for complex assembly by binding to TMD4. The two TMDs directly interact with each other and mask their respective ER-retention/retrieval signals, allowing surface transport of reporter proteins. Our data suggest a model how assembly of Pen2 into the nascent gamma-secretase complex could mask TMD-based ER-retention/retrieval signals to allow plasma membrane transport of fully assembled gamma-secretase.
γ-分泌酶在 Notch 通路和阿尔茨海默病中起着至关重要的作用。γ-分泌酶的四个亚基在内质网 (ER) 中组装，未组装的亚基通过特定的信号被保留/回收至 ER。我们在这里描述了跨膜结构域 (TMD) 4 中存在的一种新型 ER 保留/回收信号，它位于早老素 1 (γ-分泌酶的一个亚基) 中。TMD4 对于复合物的形成也是必不可少的，赋予了该结构域双重作用。同样，Pen2 的 TMD1 也是双功能的。它携带一个 ER 保留/回收信号，并通过与 TMD4 结合对复合物组装很重要。这两个 TMD 直接相互作用，掩盖了各自的 ER 保留/回收信号，从而允许报告蛋白的表面运输。我们的数据提出了一个模型，说明 Pen2 如何组装到新生的 γ-分泌酶复合物中，以掩盖基于 TMD 的 ER 保留/回收信号，从而允许完全组装的 γ-分泌酶向质膜运输。
