细菌周质分子伴侣LolA研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2020-1247

摘要/Abstract

摘要：

细菌脂蛋白是一种脂质修饰的膜蛋白,参与细胞膜合成等多种重要生理过程。脂蛋白形成过程依赖于Lol转运系统,该蛋白最先在细胞质中以前体的形式合成,然后在细胞膜上被加工为成熟脂蛋白,锚定于细菌外膜周质侧。Lol系统由LolA-E五种蛋白组成,其中脂蛋白在周质空间中依赖伴侣蛋白 LolA进行转运,LolA将脂蛋白以“mouth to mouth”的方式从LolCDE转运至LolB,进而完成脂蛋白定位。重点对周质分子伴侣LolA结构、参与的转运体系及其生物学功能进行综述,旨在通过对脂蛋白转运分子机制的理解为感染性疾病的治疗提供更多的药物靶点。

关键词: 脂蛋白, Lol转运系统, 周质分子伴侣LolA, 生物学功能

Abstract:

Bacterial lipoprotein is a lipid-modified membrane protein,which participates in many important physiological processes such as cell membrane synthesis. The formation of lipoproteins depends on the Lol transport system. The protein is first synthesized in the form of precursors in the cytoplasm,and then processed into mature lipoproteins on the cell membrane and anchored to the perimembranous sides of bacteria. Lol system is composed of 5 proteins LolA-E,among which the lipoprotein is transported by the chaperone LolA in the periplasmic space. LolA transports the lipoprotein from LolCDE to LolB in the way of “mouth to mouth”,thereby completing the localization of lipoprotein. This review focuses on the structure,involved transport system and biological functions of periplasmic molecular chaperone LolA,aiming to provide more drug targets for the treatment of infectious diseases by understanding the molecular mechanism of lipoprotein transport.

Key words: bacterial lipoproteins, Lol transport system, periplasmic chaperone LolA, biological function

贺小丽, 郭磊周, 韩佳慧, 唐殷, 袁媛, 代其林, 平淑珍, 江世杰. 细菌周质分子伴侣LolA研究进展[J]. 生物技术通报, 2021, 37(8): 275-283.

HE Xiao-li, GUO Lei-zhou, HAN Jia-hui, TANG Yin, YUAN Yuan, DAI Qi-lin, PING Shu-zhen, JIANG Shi-jie. Research Progress on Bacterial Periplasmic Chaperone LolA[J]. Biotechnology Bulletin, 2021, 37(8): 275-283.

图/表 5

图1 大肠杆菌LolA的晶体结构[22] LolA的疏水腔由开放的β-桶和α-螺旋盖子组成,也是脂质的结合位点;LolA的C-末端环由短α-螺旋和第12位β-链组成,能够正确地将脂蛋白递送至OM

Fig. 1 Crystal structure of Escherichia coli LolA[22] The hydrophobic cavity of LolA is composed of an open β-barrel and an α-helical lid,which is also a binding site for lipids;the C-terminal loop of LolA is composed of a short α-helix and a twelfth β-strand,which can correctly combine lipoprotein delivery to OM

图2 Lol系统介导的脂蛋白转运和外膜锚定[22] a：脂蛋白首先置于LolE中（1）,然后转移至位于LolC上的LolA（2）。当LolCDE结合脂蛋白时,LolA和LolCDE之间的相互作用增加（实线箭头）。然后LolA以ATP依赖性方式与脂蛋白形成亲水性复合物,同时打开LolA疏水腔（3）。b：在穿过周质空间后,LolA和LolB以“mouth to mouth”的方式互作将脂蛋白从LolA转移至LolB（4）,最终定位到外膜

Fig. 2 Lipoprotein transport and outer membrane anchoring mediated by the Lol system[22] a：Lipoprotein is first placed in LolE（1）,and then transferred to LolA located on LolC（2）. When LolCDE binds to lipoproteins,the interaction between LolA and LolCDE increases（solid arrow）. Then LolA forms a hydrophilic complex with lipoproteins in an ATP-dependent manner,and opens the hydrophobic cavity of LolA at the same time（3）. b：After passing through the periplasmic space,LolA and LolB interact in a “mouth to mouth” manner to transfer lipoproteins from LolA to LolB（4）,and finally locate to the outer membrane

图3 LolA的晶体结构与LolC的周质域结合[30] A：LolA - LolC 复合体的总体结构;B：互作界面视图。LolC 和 LolA 分别以青色和金色表示。属于 Hook 和 Pad 的残留物显示为紫色和橙色。与 LolC交互的内容以棒状显示

Fig. 3 Crystal structure of LolA is combined with the periplasmic domain of LolC[30] A：The overall structure of the LolA-LolC complex. B：Interaction interface view. LolC and LolA are represented in cyan and gold,respectively. The residue belonging to Hook and Pad is shown in purple and orange. The content that interacts with LolC is displayed in a bar shape

图4 脂蛋白在LolA和LolB上的转运模型[36] LolA 和 LolB 分别用绿色和蓝色的桶状表示,红色代表酰基链。第 1 步,从内膜周质侧的 LolCDE 获得一种脂蛋白,LolA 经过构象变化并使其疏水腔适应了 1-3 种脂蛋白酰基链。第 2 步,脂蛋白-LolA 复合物与锚定在外膜上的LolB 相互作用,在该复合物中,LolA 和 LolB 形成一个疏水的、类似通道的结构。第 3 步,在脂蛋白酰基链通过这两个蛋白形成的疏水通道从 LolA 转移到 LolB

Fig. 4 Transport model of lipoprotein on LolA and LolB[36] LolA and LolB are represented by green and blue barrels,respectively,and red represents the acyl chain. Step 1: a lipoprotein is obtained from LolCDE on the periplasmic side of the inner membrane. LolA undergoes a conformational change and adapts its hydrophobic cavity to 1 to 3 lipoprotein acyl chains. Step 2: the lipoprotein-LolA complex interacts with the LolB anchored on the outer membrane. In the complex,LolA and LolB form a hydrophobic,channel-like structure. Step 3: the acyl chain of the lipoprotein is transferred from LolA to LolB through the hydrophobic channel formed by these two proteins

图5 LolA疏水腔中BLP的结合模式[47] A：左：启动配置,其中 BLP（黄色）位于 LolA（青色）腔的外部。右上：BLP 的3个脂尾在腔口附近结合的结合方式。右下：一个脂尾在腔深,而另两个在腔口处;B：3个独立模拟的 BLP 脂尾和 F90 残基之间的最小距离（如插图中范德瓦尔斯表示法所示）

Fig.5 Binding mode of BLP in the hydrophobic cavity of LolA[47] A：Left：Start configuration,where BLP（yellow）is located outside the LolA（cyan）cavity. Upper right：The combination of the three fat tails of BLP near the mouth of the cavity. Lower right：One fat tail is deep in the cavity,and the other two are at the mouth of the cavity. B：The minimum distance between the three independently simulated BLP fat tails and F90 residues（as shown in the illustration by Van der Waals notation）

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