Mikhail Bogdanov
Professor
休斯敦德克萨斯大学健康科学中心
McGovern Medical School
Department of Biochemistry and Molecular Biology
Topobiology (lipid and protein topogenesis) and bioconformatics
Lipid-assisted dynamic membrane protein topogenesis.
The goal of the first project in the lab is to investigate the molecular mechanism and physiological significance of lipid-dependent membrane protein topogenesis by testing a novel Charge Balance Rule for different proteins and lipid profilesin vivoandin vitro为了建立生理significance of conformational and topological heterogeneity, co-translational, post-translational and post-insertional dynamic changes in topological organization of membrane proteins in bacterial, “healthy” mammalian cells and its organelles, resting and stressed cancer cells. The subaim of this project is to test the Charge Balance Rule在硅中and verify the concept of the funnel-like intermolecular energy landscape of lipid–protein transient interactions by using of a series of in vivo “translocation force” measurements and computational experiments. The aim of this project is also to test Charge Balance Rule for polytopic membrane protein assembly in cancer cells where changes in lipid asymmetry and external environment occur regularly due to development of this severe disease. Whether transmembrane protein topology in cancer cells is affected by the changes in lipid asymmetry and charge distribution across the membrane is still unknown, thus Charge Balance Rule will be tested at first time for eukaryotic membrane protein.
动态膜不对称。
为什么细胞膜是（A）对称的？当将蛋白质和脂质合成在细胞中时，它们会以不对称的方式插入膜中。这是因为它们主要插入遗传和结构预定义的不对称方式并控制脂质的不对称分布吗？还是可以实现净脂质不对称性来帮助平衡膜蛋白的不对称电荷并根据积极的内部规则将其定向？
膜中的脂质不对称性是多种因素的结果，包括脂质的物理特性，这些脂质的物理性能决定了它们自发“翻转或不翻转”其极性头组穿过疏水膜内部的能力以及活性的磷脂泵（ATP依赖于ATP依赖的Flippases Flippases））和非ATP独立的串联酶，它们能够创建或消散跨膜脂质不对称并保持膜的非平衡热力学状态。生物膜含有分别连续合成膜脂质和蛋白质的酶和机器，仅在双层的一个胞质小叶上。因此，可以将脂质不对称性用于代谢控制，以平衡合成和触发器的净速率，并将双层化学和物理性质调整为自发反应。
We are still far from full understanding of the physiological significance and detailed molecular mechanisms by which membrane phospholipid asymmetry is generated, maintained and modulated. We pioneered methods to interrogate lipid enzymology and individual phospholipid topography (transmembrane sidedness) using novel assays to establish the function of individual lipid enzymes and lipids in such complex processes as translocation of lipids and proteins across the lipid bilayer, folding and topogenesis, cancerogenesis, sickle cell disease and chronic kidney disease。我们利用了具有不同膜穿透和化学特性的最近载体化学和荧光探针来报告一种新的方法，以使用辐射，质谱法和分光光度法方法来确定氨基磷脂的头部组和酰基不对称性。这种新型方法适合研究氨基脂蛋白（磷脂酰辛林（PS）（PS）和磷脂酰乙醇胺（PE）的稳态分布和动力学，任何细胞细胞器（红细胞，外部，外胞体，凋亡体，任何单次单膜系统）或单膜系统（包括liptoplasts等）中的磷脂酰乙醇胺（PE）（PE），使用辐射，分光光度计或质谱法的内膜（IM）或外膜（OM）（OM）。这种新方法适合研究稳态分布和氨基酚（磷脂酰氧基氧基氧基盐酸碱（PS））的动力学（PS）和磷脂酰乙醇胺（PE）（红细胞，外泌体，凋亡人体，线粒体，线粒体，线粒体，线粒体）中的磷脂酰乙醇胺（PE）etc。) surrounded by a single membrane. We demonstrate that the IM大肠杆菌、鼠疫pseudotuberculosisis asymmetric with 75%/25% (cytoplasmic/periplasmic leaflet) distribution of PE in rod-shaped cells and an opposite distribution in filamentous cells. Moreover PE and CL are dynamically redistributed across IM to follow or direct the changes in bacterial shape.
Whether such flippase-less or “lipid only” “passive” mechanism of generation and maintenance of lipid asymmetry exists?
What is the reason for the cell membrane to be (a)symmetric in biogenic- and non-biogenic cells, healthy and cancer cells?
脂蛋白。
The goal of this project is to test a hypothesis that specific lipids (cold and shock lipidsin this case) can optimize protein function and conformation and promote proper folding at low or elevated temperatures i.e. act in the way molecular chaperones of protein origin do. The aim of this project is to test a hypothesis that conformation of outer membrane b-barrel porins from pathogenic bacteria may adapt toin vivo磷脂成分的变化，以优化或调节其活性或折叠和组装途径。要测试的主要假设是，具有不同分子结构和热态行为的内源性脂质起作用，用作分子伴侣，影响模型通道形成的寡聚寡聚蛋白porin yompf的构象成熟，从革兰氏阴性型蛋白质蛋白porin yompf。Y. pseudotuberculosis。该项目的第二个目的是研究细菌包膜内甘油磷脂不对称性，外部化和重塑在细菌对抗生素的耐药性发展以及抵抗宿主先天免疫力的能力方面的作用。
细菌包膜重塑和对抗生素和先天免疫系统的抗性的发展。
The goal of this project is to investigate the physiological significance of the “lipid” genes multiplicity and lipid interchangeability in Gram-negative bacteria and the role of transmembrane phospholipid asymmetry and remodeling within bacterial envelope in the development of resistance to antibiotics, intracellular survival and ability to resist innate immunity of infected host.
脂质和Secyeg cllessocon。
该项目的目的是研究膜磷脂在易转克辅助且无助的蛋白易位和膜蛋白插入中的作用。膜磷脂可能会通过影响其构象并与分布在整个易位或插入多肽或间接插入易位和插入机器的构素信号的构象和相互作用来直接对新生蛋白发挥作用。
Keywords: Membrane protein · Phospholipid · Protein Topogenesis · Charge Balance Rule · Protein folding · Lipochaperones · Envelope remodeling · Antibiotic resistance · Lipid asymmetry · Translocon
McGovern Medical School Faculty
Education & Training
博士- 苏联科学院 - 1989年