Department of Biochemistry and Molecular Biology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
J Cell Sci. 2021 Apr 15;134(8). doi: 10.1242/jcs.255877. Epub 2021 Apr 28.
TMEM41B and VMP1 are endoplasmic reticulum (ER)-localizing multi-spanning membrane proteins required for ER-related cellular processes such as autophagosome formation, lipid droplet homeostasis and lipoprotein secretion in eukaryotes. Both proteins have a VTT domain, which is similar to the DedA domain found in bacterial DedA family proteins. However, the molecular function and structure of the DedA and VTT domains (collectively referred to as DedA domains) and the evolutionary relationships among the DedA domain-containing proteins are largely unknown. Here, we conduct a remote homology search and identify a new clade consisting mainly of bacterial proteins of unknown function that are members of the Pfam family PF06695. Phylogenetic analysis reveals that the TMEM41, VMP1, DedA and PF06695 families form a superfamily with a common origin, which we term the DedA superfamily. Coevolution-based structural prediction suggests that the DedA domain contains two reentrant loops facing each other in the membrane. This topology is biochemically verified by the substituted cysteine accessibility method. The predicted structure is topologically similar to that of the substrate-binding region of Na+-coupled glutamate transporter solute carrier 1 (SLC1) proteins. A potential ion-coupled transport function of the DedA superfamily proteins is discussed. This article has an associated First Person interview with the joint first authors of the paper.
TMEM41B 和 VMP1 是内质网 (ER) 定位的多跨膜蛋白，对于真核生物中的 ER 相关细胞过程（如自噬体形成、脂滴动态平衡和脂蛋白分泌）是必需的。这两种蛋白质都有一个 VTT 结构域，类似于细菌 DedA 家族蛋白中的 DedA 结构域。然而，DedA 和 VTT 结构域（统称为 DedA 结构域）的分子功能和结构以及包含 DedA 结构域的蛋白质之间的进化关系在很大程度上是未知的。在这里，我们进行了远程同源搜索，鉴定出一个新的分支，主要由功能未知的细菌蛋白组成，这些蛋白是 Pfam 家族 PF06695 的成员。系统发育分析表明，TMEM41、VMP1、DedA 和 PF06695 家族形成了一个具有共同起源的超家族，我们称之为 DedA 超家族。基于共进化的结构预测表明，DedA 结构域包含两个在膜中彼此相对的折返环。这种拓扑结构通过取代半胱氨酸可及性方法在生化上得到了验证。预测的结构在拓扑上与 Na+-偶联谷氨酸转运体溶质载体 1 (SLC1) 蛋白的底物结合区域相似。讨论了 DedA 超家族蛋白的潜在离子偶联转运功能。本文附有对论文的共同第一作者的第一人称采访。
