Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
Nat Commun. 2021 Jan 25;12(1):568. doi: 10.1038/s41467-020-20625-y.
The endoplasmic reticulum (ER) network consists of tubules with high membrane curvature in cross-section, generated by the reticulons and REEPs. These proteins have two pairs of trans-membrane (TM) segments, followed by an amphipathic helix (APH), but how they induce curvature is poorly understood. Here, we show that REEPs form homodimers by interaction within the membrane. When overexpressed or reconstituted at high concentrations with phospholipids, REEPs cause extreme curvature through their TMs, generating lipoprotein particles instead of vesicles. The APH facilitates curvature generation, as its mutation prevents ER network formation of reconstituted proteoliposomes, and synthetic L- or D-amino acid peptides abolish ER network formation in Xenopus egg extracts. In Schizosaccharomyces japonicus, the APH is required for reticulon's exclusive ER-tubule localization and restricted mobility. Thus, the TMs and APH cooperate to generate high membrane curvature. We propose that the formation of splayed REEP/reticulon dimers is responsible for ER tubule formation.
内质网（ER）网络由横截面具有高膜曲率的小管组成，由网蛋白和 REEP 产生。这些蛋白质有两对跨膜（TM）片段，后面跟着一个两亲螺旋（APH），但它们如何诱导曲率还不清楚。在这里，我们表明 REEP 通过在膜内相互作用形成同源二聚体。当过量表达或在高浓度与磷脂重新构成时，REEPs 通过它们的 TM 引起极端曲率，产生脂蛋白颗粒而不是囊泡。APH 促进曲率的产生，因为其突变阻止了重新构成的蛋白脂质体中 ER 网络的形成，而合成的 L-或 D-氨基酸肽则会在非洲爪蟾卵提取物中消除 ER 网络的形成。在裂殖酵母中，APH 对于网蛋白的内质网小管的特异性定位和受限运动是必需的。因此，TM 和 APH 共同产生高的膜曲率。我们提出，展开的 REEP/网蛋白二聚体的形成负责 ER 小管的形成。
