Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix
Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix
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DOI：
10.1016/j.molcel.2016.06.032
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发表时间：
2016-08-18
期刊：
影响因子：
16
通讯作者：
Ye, Jin
中科院分区：
文献类型：
--
作者：
Chen, Qiuyue;Denard, Bray;Ye, Jin
TM4SF20（跨膜4 L6家族20）是一种多位膜蛋白，可抑制CREB 3L1（cAMP反应元件结合蛋白3样1）的蛋白水解加工，CREB 3L1是一种膜结合转录因子，可阻断细胞分裂并激活胶原蛋白合成。在这里，我们报告说，神经酰胺刺激CREB3L1裂解反转TM4SF20在膜中的方向。在不存在神经酰胺的情况下，TM4SF 20的第一跨膜螺旋的N末端插入内质网（ER）腔中。这种易位需要TRAM2（易位链相关膜蛋白2），一种含有假定的神经酰胺相互作用结构域的膜蛋白。在神经酰胺存在下，TM4SF 20的第一跨膜结构域的N末端暴露于胞质溶胶。因此，TM4SF20的膜拓扑结构被反转，并且这种形式的TM4SF20刺激CREB3L1裂解。在神经酰胺存在下，TM4SF20的易位是TRAM2非依赖性的。我们将这种引起膜拓扑结构调节性倒位的机制称为“调节性交替易位”。"
TM4SF20 (transmembrane 4 L6 family 20) is a polytopic membrane protein that inhibits proteolytic processing of CREB3L1 (cAMP response element-binding protein 3-like 1), a membrane-bound transcription factor that blocks cell division and activates collagen synthesis. Here we report that ceramide stimulates CREB3L1 cleavage by inverting the orientation of TM4SF20 in membranes. In the absence of ceramide, the N terminus of the first transmembrane helix of TM4SF20 is inserted into the endoplasmic reticulum (ER) lumen. This translocation requires TRAM2 (translocating chain-associated membrane protein 2), a membrane protein containing a putative ceramide-interacting domain. In the presence of ceramide, the N terminus of the first transmembrane domain of TM4SF20 is exposed to cytosol. Consequently, the membrane topology of TM4SF20 is inverted, and this form of TM4SF20 stimulates CREB3L1 cleavage. In the presence of ceramide, translocation of TM4SF20 is TRAM2-independent. We designate this mechanism-causing regulated inversion of the membrane topology as "regulated alternative translocation."