Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell Rep. 2013 Sep 12;4(5):921-30. doi: 10.1016/j.celrep.2013.07.050. Epub 2013 Sep 5.
Insulin homeostasis in pancreatic β cells is now recognized as a critical element in the progression of obesity and type II diabetes (T2D). Proteins that interact with insulin to direct its sequential synthesis, folding, trafficking, and packaging into reserve granules in order to manage release in response to elevated glucose remain largely unknown. Using a conformation-based approach combined with mass spectrometry, we have generated the insulin biosynthetic interaction network (insulin BIN), a proteomic roadmap in the β cell that describes the sequential interacting partners of insulin along the secretory axis. The insulin BIN revealed an abundant C2 domain-containing transmembrane protein 24 (TMEM24) that manages glucose-stimulated insulin secretion from a reserve pool of granules, a critical event impaired in patients with T2D. The identification of TMEM24 in the context of a comprehensive set of sequential insulin-binding partners provides a molecular description of the insulin secretory pathway in β cells.
胰腺β细胞中的胰岛素稳态现在被认为是肥胖和 2 型糖尿病（T2D）进展的关键因素。与胰岛素相互作用以指导其顺序合成、折叠、运输和包装到储备颗粒中，以响应升高的葡萄糖管理释放的蛋白质在很大程度上尚不清楚。我们使用基于构象的方法结合质谱法，生成了胰岛素生物合成相互作用网络（胰岛素 BIN），这是β细胞中的蛋白质组学路线图，描述了沿着分泌轴的胰岛素的顺序相互作用伙伴。胰岛素 BIN 揭示了一种丰富的含 C2 结构域的跨膜蛋白 24（TMEM24），它可以从储备颗粒池中管理葡萄糖刺激的胰岛素分泌，这是 T2D 患者受损的关键事件。在一套全面的顺序胰岛素结合伙伴的背景下鉴定 TMEM24 为β细胞中的胰岛素分泌途径提供了分子描述。
