Evolution and insights into the structure and function of the DedA superfamily containing TMEM41B and VMP1
Evolution and insights into the structure and function of the DedA superfamily containing TMEM41B and VMP1
复制标题
DOI：
10.1242/jcs.255877
复制
发表时间：
2021-04-01
影响因子：
4
通讯作者：
Mizushima, Noboru
中科院分区：
文献类型：
--
作者：
Okawa, Fumiya;Hama, Yutaro;Mizushima, Noboru
TMEM 41 B和VMP 1是内质网（ER）定位的多跨膜蛋白，其是真核生物中ER相关细胞过程（例如自噬体形成、脂滴稳态和脂蛋白分泌）所需的。这两种蛋白质都具有VTT结构域，其类似于在细菌DedA家族蛋白质中发现的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含DedA结构域蛋白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性搜索，并确定了一个新的Glade主要由Pfam家族PF 06695成员的未知功能的细菌蛋白组成。系统发育分析表明，TMEM 41、VMP 1、DedA和PF 06695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。基于协同进化的结构预测表明，DedA结构域包含两个在膜中相互面对的折返环。这种拓扑结构的生物化学验证取代半胱氨酸的可及性方法。预测的结构是拓扑相似的Na+-耦合谷氨酸转运溶质载体1（SLC 1）蛋白质的底物结合区。本文讨论了DedA超家族蛋白质的一个潜在的离子耦合转运功能，并对该论文的第一作者进行了第一人称访谈。
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 Glade 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.