Caveolae are Q-shaped invaginations of the plasma membrane, found in many types of cells [1]. Caveolae are enriched in cholesterol, and have a membrane composition similar to that of lipid rafts [2]. In addition, caveolae show a high concentration of the protein caveolin, a hairpin-structured membrane protein possessing a hydrophobic domain [32 amino acids (AA), flanked by two hydrophilic termini (N-terminal: 101 AA, C-terminal: 43 AA)] [3]. Both termini of caveolin extend from the cytosolic side of the membrane, conferring a strong asymmetrical structure to the caveolar domain. The goal of this chapter is to provide an overview of the possible physical effects that can stem from both of these characteristics of caveolae, namely the composition difference with the rest of the plasma membrane ("raft-aspect") and their patent asymmetry ("hairy-aspect").

Although Caveolae were first observed more than 50 years ago, many of their properties and functions remain unknown. Caveolae formation seems to require the presence of the protein caveolin [4] and is very dependent on the cholesterol level in the cell [5]. There is also evidence that caveolin is coupled to other types of membrane deformation (e.g., tubular structures in endothelial cells [6]). These are strong indications that at least some biological functions of caveolae rely heavily upon their biophysical properties. Plasma membranes typically resist bending, and the formation of membrane invaginations requires the action of mechanical forces on the membrane. Even though caveolae are very complex biochemical objects, they are bound to obey the laws of physics. We must therefore understand the origin of the forces at play in the formation of the invaginations if we are to understand how, and why, caveolae form. As we make progress towards this we may gain important insights into the biological functions of caveolae. Indeed, since caveolae are inherently coupled to the mechanical state of the plasma membrane, one may envision that the cell has taken advantage of this coupling, and may use caveolae as mechano-sensors or mechano-regulators for the plasma membrane. Before discussing these possibilities in Section 2.6, we will first review some of the physical concepts behind the formation and structure of mem brane domains and how this relates to the physical properties of membrane proteins.

The description present ed relies on coarse-grained physical models where the molecular structure of the membrane and proteins is only taken into account in an approximate way. This is justified by the fact that caveolae (of size ~100 nm) are much larger than the size of the individual caveolin proteins and of the thickness of the plasma membrane (~5 nm). This physical description is based on the well-known properties of fluid bilayer membranes, described in Section 2.2. Following this, two different points of view are taken to describe the formation and invagination of caveolae. In Section 2.3, caveolae are regarded as membrane domains that are chemically immiscible in the plasma membrane. This neglects effects associated directly with the details of domain composition. It is assumed there that membrane phase separation into domains does n't depend on the mechanical properties of the membrane, although the domain shape might. This description somewhat overlooks the importance of the protein caveolin in the formation of caveolae. In an attempt to approximate the complexity of the biological membrane, theoretical physicists have studied the behavior of membrane inclusions, and in particular how protein aggregation is coupled to membrane deformation, and viceversa. These models are briefly overviewed in Section 2.4, and applied to the particular case of caveolin aggregation in caveolar membranes in Section 2.5, by taking some account of the protein structure. The final section includes a discussion of how such a description relates to the "life" of caveolae at the plasma membrane of cells. Finally, we speculate on further possible biological functions of caveolae.

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Essentials of Human Physiology

Essentials of Human Physiology

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