Huber Tobias B, Schermer Bernhard, Müller Roman Ulrich, Höhne Martin, Bartram Malte, Calixto Andrea, Hagmann Henning, Reinhardt Christian, Koos Fabienne, Kunzelmann Karl, Shirokova Elena, Krautwurst Dietmar, Harteneck Christian, Simons Matias, Pavenstädt Hermann, Kerjaschki Dontscho, Thiele Christoph, Walz Gerd, Chalfie Martin, Benzing Thomas
Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17079-86. doi: 10.1073/pnas.0607465103. Epub 2006 Nov 1.
The prohibitin (PHB)-domain proteins are membrane proteins that regulate a variety of biological activities, including mechanosensation, osmotic homeostasis, and cell signaling, although the mechanism of this regulation is unknown. We have studied two members of this large protein family, MEC-2, which is needed for touch sensitivity in Caenorhabditis elegans, and Podocin, a protein involved in the function of the filtration barrier in the mammalian kidney, and find that both proteins bind cholesterol. This binding requires the PHB domain (including palmitoylation sites within it) and part of the N-terminally adjacent hydrophobic domain that attaches the proteins to the inner leaflet of the plasma membrane. By binding to MEC-2 and Podocin, cholesterol associates with ion-channel complexes to which these proteins bind: DEG/ENaC channels for MEC-2 and TRPC channels for Podocin. Both the MEC-2-dependent activation of mechanosensation and the Podocin-dependent activation of TRPC channels require cholesterol. Thus, MEC-2, Podocin, and probably many other PHB-domain proteins by binding to themselves, cholesterol, and target proteins regulate the formation and function of large protein-cholesterol supercomplexes in the plasma membrane.
禁蛋白（PHB）结构域蛋白是一类膜蛋白，可调节多种生物活性，包括机械感觉、渗透稳态和细胞信号传导，尽管这种调节机制尚不清楚。我们研究了这个大蛋白家族的两个成员，秀丽隐杆线虫触觉敏感性所需的MEC-2，以及参与哺乳动物肾脏滤过屏障功能的蛋白足突蛋白，发现这两种蛋白都能结合胆固醇。这种结合需要PHB结构域（包括其中的棕榈酰化位点）以及将蛋白质连接到质膜内小叶的N端相邻疏水结构域的一部分。通过与MEC-2和足突蛋白结合，胆固醇与这些蛋白所结合的离子通道复合物相关联：MEC-2对应的是DEG/ENaC通道，足突蛋白对应的是TRPC通道。机械感觉的MEC-2依赖性激活和TRPC通道的足突蛋白依赖性激活都需要胆固醇。因此，MEC-2、足突蛋白，可能还有许多其他PHB结构域蛋白，通过自身结合、胆固醇结合和与靶蛋白结合，调节质膜中大型蛋白-胆固醇超复合物的形成和功能。
