Membrane Inclusions

Membrane proteins have hydrophobic regions inserted within the lipid bilayer, and this insertion may perturb the bilayer structure. For example, a mismatch in thickness between the hydrophobic core of the protein and that of the bilayer has an associated energy cost. It implies either that some hydrophobic residues are left unshielded from contact with water, or that the membrane (or the protein) changes its thickness to obtain a good match [18]. The consequence of hydrophobic mismatch may be protein clustering, as shown in Figure 2.3a,b. Clustering may occur even in the absence of direct (specific) interaction between the proteins, as the result of an effective attraction mediated by the membrane. As shown in Figure 2.3a,b, the membrane order is locally perturbed in the vicinity of the inclusion (the figure shows a local stretching of the lipid tails, to accommodate the hydro-phobic thickness of the membrane). Bringing two inclusions together reduces the membrane area that needs to be perturbed and hence reduces the energy of membrane deformation. The result of this is an effective force that brings the proteins together.

An important phenomenon in the context of caveolae and their asymmetric membranes is when protein clustering is coupled to a change of membrane morphology. This can be expected for very asymmetric proteins, or for peripheral proteins that mostly extend on one side of the membrane. Such asymmetric membrane proteins can be thought of as imprinting a local spontaneous curvature (the Co term in Eq. (2) to the neighboring membrane (Fig. 2.3c). The membrane is locally curved near the protein, which again leads to a frustration of the bilayer order. As it is the case for hydrophobic mismatch, some of the frustration can be released if the proteins aggregate. In this case however, the concentration of a large number of proteins over a limited membrane area leads to a morphological change of the membrane, which adopts the preferred curvature of the proteins (Fig. 2.3d). As will be discussed in Section 2.5, this phenomenon, called "curvature instability" in the physics literature [19], is likely to play an important part in the formation of caveolae. The caveolin proteins found in caveolae are very good candidates for such large morphological changes for two reasons. On the one hand, both their hydro-

Hydrophobic Mismatch

Fig. 2.3 Sketch of the aggregation of membrane proteins induced by an hydrophobic mismatch. (a) The mismatch imposes a perturbation of the bilayer structure around the protein. (b) The aggregation of two such proteins reduces the area of the perturbed membrane, and is energetically favorable.

(c,d) Sketch of the aggregation of membrane proteins induced by an asymmetric coupling with the membrane. The asymmetric membrane perturbation around each inclusion (c), is reduced by protein aggregation (d), which induce a large-scale deformation in the membrane region with high protein density.

Fig. 2.3 Sketch of the aggregation of membrane proteins induced by an hydrophobic mismatch. (a) The mismatch imposes a perturbation of the bilayer structure around the protein. (b) The aggregation of two such proteins reduces the area of the perturbed membrane, and is energetically favorable.

(c,d) Sketch of the aggregation of membrane proteins induced by an asymmetric coupling with the membrane. The asymmetric membrane perturbation around each inclusion (c), is reduced by protein aggregation (d), which induce a large-scale deformation in the membrane region with high protein density.

phobic termini face the cytoplasm, which makes their interaction with the neighboring membrane very asymmetric. A similar situation can to some extent be reproduced in artificial systems, by mixing bilayer-forming lipids with hydrophilic polymers (typically polyethylene glycol) with a hydrophobic anchor attached. Lipid membranes with a grafted (but mobile) polymer chain can be obtained in such manner, and it has been shown theoretically [20], and observed experimentally [21], that such a membrane can exhibit a phase separation. Another reason to expect membrane deformation near caveolin proteins is the fact that they are known to form homo-oligomers of about 15 proteins. This is due to specific biochemical interactions between caveolin via a short section of the N-terminal cytoplasmic domain, quite close to the transmembrane domain [3]. As shown in Section 2.5, this oligomerization may have much to do with the success of caveolin in aggregating and promoting membrane invagination. By concentrating the caveo-lin, oligomerization also concentrates the effect of the membrane asymmetry over a small membrane area, creating a large asymmetric pressure.

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