Stretching the Definition of a Lipid Bilayer: Elasticity's Role in Protein and Lipid Organization
Stretching the Definition of a Lipid Bilayer: Elasticity's Role in Protein and Lipid Organization
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扩展脂质双层的定义：弹性在蛋白质和脂质组织中的作用
DOI：
10.7907/q0r5-k353
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发表时间：
2009
影响因子：
3.3
通讯作者：
T. Ursell
中科院分区：
文献类型：
--
作者：
T. Ursell
中心法则构成了以聚合物语言表述的分子生物学的基础；所有的关键参与者都在那里--DNA、RNA、蛋白质--至少看起来是这样。然而，一类对生命至关重要的生物合成分子经常被忽视：脂类。这些两亲性分子表现出许多奇怪的性质，是细胞在不同的化学环境中区分自我和非自我的能力所不可或缺的。脂类自组装成长宽比为1000比1或更多的二维双层流体，能够自我修复并弯曲成极其复杂的形状。在细胞内，膜允许许多化学上不同的隔间，对于新陈代谢、蛋白质组装、基因组管理和细胞分裂是必不可少的。由于数百种不同类型的脂类和蛋白质在给定的膜上相互作用，我们有很多东西需要了解膜是如何调节物质进出细胞的。显然，分子水平的细节是我们理解这些体系不可或缺的一部分，然而，在介观水平上，膜表现出某些机械效应，用于组织脂质和蛋白质，这是本论文的主要研究内容。我们首先建立一个双层的弹性模型，其中嵌入的蛋白质使周围的膜变形，并产生免费的能量成本。这使得双层的机械属性可以影响嵌入蛋白质的构象。我们在细菌的机械感觉的背景下探索这种联系，以及开发允许双层机制对经典的电压门控离子通道的结构进行评论的方法。除了影响构象偏好，这些相同的变形具有有限的长度尺度，导致嵌入蛋白之间的相互作用。根据蛋白质形状的不同，这些相互作用可能是吸引的，也可能是排斥的，可能会对蛋白质施加扭矩，提供一种特定形状的寡聚机制，重要的是允许蛋白质利用双层作为构象信息的通用通信器。以细菌机械敏感通道MSCL为例，从蛋白质平均间距、二聚化、构象协同性和多聚体蛋白质组装的可能途径等方面讨论了这些弹性相互作用的影响。在接下来的章节中，双层弹性被用来阐明脂质本身的大规模组织。生物膜可能有多个流体和脂相，其中饱和脂类和胆固醇的隔离形成脂域。我们发现，超过一定临界尺寸的结构域的形成会导致形态转变为“凹陷”相，这会打开排斥的、弹性的相互作用，从而在空间上组织结构域，并严重抑制结构域的合并。这为在较短的长度尺度和较长的时间尺度上维持脂类的横向异质性提供了一种机制。我们进一步观察到离散的转变为“萌芽”的结构域形态，并发展了一套平坦、凹陷和萌芽结构域之间的解释性能量转换规则。我们证明，这些形态及其伴随的转变导致了膜中一种独特的依赖于结构域大小的运输。此外，我们使用囊泡的机制来模拟通过通道蛋白进行的渗透调节，并在保守的表面积和体积的背景下发展了一个理论和实验框架来研究高亲性蛋白结合背景下的膜黏附。
The Central Dogma forms the foundation of molecular biology couched in polymer language; all the key players are there — DNA, RNA, protein — or so it would seem. Yet one class of biologically synthesized molecules, crucial for life, is often over looked: lipids. These amphiphilic molecules exhibit a number of strange properties, integral to the cells ability to separate self from non-self in a chemically diverse environment. Lipids self-assemble into two-dimensional bi-layered fluids with aspect ratios of a thousand to one or more, capable of self-healing and bending into extraordinarily complex shapes. Within the cell, membranes allow for numerous chemically-distinct compartments, essential for metabolism, protein assembly, genome management, and cell division. With literally hundreds of different kinds of lipids and proteins interacting on a given membrane, we have much to learn about how membranes regulate the flow of materials into and out of cells. Clearly, molecular level detail is integral to our understanding of these systems, however, on the mesoscopic level membranes exhibit certain mechanical effects that serve to organize lipids and proteins, the study of which forms the bulk of this dissertation. We start by building an elastic model of bilayers, where embedded proteins deform the surrounding membrane and incur a free energy cost. This allows the mechanical attributes of the bilayer to influence the conformation of embedded proteins. We explore this connection in the context of mechanosensation in bacteria, as well as developing methods that allow bilayer mechanics to comment on the structure of classically voltage-gated ion channels. In addition to affecting conformational preferences, these same deformations have a finite length-scale that results in interactions between embedded proteins. Depending on the protein shape, these interactions can be attractive or repulsive, may exert torques on proteins, provide for a mechanism of shape-specific oligomerization, and importantly allow proteins to utilize the bilayer as a generic communicator of conformational information. The effects of these elastic interactions are discussed in the context of mean protein spacing, dimerization, conformational cooperativity, and likely pathways to multi-mer protein assembly, with the bacterial mechanosensitive channel MscL as a structural example. In subsequent chapters, bilayer elasticity is used to shed light on the large-scale organization of lipids themselves. Biological membranes likely have multiple fluid, lipid phases, where sequestration of saturated lipids and cholesterol form lipid domains. We found that formation of domains above a certain critical size induces morphological transitions to a ‘dimpled’ phase which turns on repulsive, elastic interactions that serve to spatially organize domains as well as severely inhibit domain coalescence. This provides a mechanism for the maintenance of lipid lateral heterogeneity on relatively short length-scales and long time scales. We further observed discrete transitions to a ‘budded’ domain morphology and developed a set of interpretive energetic transition rules between flat, dimpled and budded domains. We demonstrate that these morphologies and their attendant transitions lead to a unique form of domain-size-dependent transport in membranes. Further, we employ the mechanics of vesicles to model osmoregulation via channel proteins, and in the setting of conserved surface area and volume to develop a theoretical and experimental framework to study membrane adhesion in the context of the homophilic protein binding.
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DOI：
--
发表时间：
2002
期刊：
Annual review of biophysics and biomolecular structure
影响因子：
--
作者：
R. Spencer;D. Rees
通讯作者：
R. Spencer;D. Rees
影响因子：
4
作者：
Veatch, Sarah L.;Cicuta, Pietro;Baird, Barbara
通讯作者：
Baird, Barbara
DOI：
10.1073/pnas.0810187105
发表时间：
2008-12-09
影响因子：
11.1
作者：
Schmidt, Daniel;MacKinnon, Roderick
通讯作者：
MacKinnon, Roderick
影响因子：
10.5
作者：
KAMADA, Y;JUNG, US;LEVIN, DE
通讯作者：
LEVIN, DE
影响因子：
3.4
作者：
Olbrich, K;Rawicz, W;Evans, E
通讯作者：
Evans, E