The mosaic-like organization of lipid structures - that is, the assembly of lipids with similar physico-chemical character (saturation, length, etc.) - into distinct domains  plays an important role in the formation of both small- and large-scale protein assemblies. The lipid domain structure of the plasma membrane may cause selective accumulation of membrane proteins (or their exclusion from distinct membrane areas) through preferential interaction of the membrane-interacting region of a given protein with a select class of lipids . Lipid rafts, enriched in cholesterol and glycosphingolipids, are a special type of lipid domains [4,7]. Lipid rafts were shown to accumulate a set of membrane proteins as well as cytosolic signaling elements, and were proposed to act as specialized signaling compartments [13,19-23]. There are several vehicles that may help target proteins into lipid rafts:
• a shell of annular lipids encasing the transmembrane segment of proteins ;
• the addition of a GPI-anchor or saturated acyl chains via post-translational modification [25-28]; and
• interactions with proteins having a high affinity to the lipid raft environment.
Rafts are complex and dynamic structures which vary both in size and protein content . By enabling the dynamic association/reassociation of proteins residing within the same domain, lipid rafts provide a platform for their functional cooperation. The dynamic exchange of components between rafts with different composition (or between raft and non-raft regions) as well as the aggregation of smaller rafts, raft "microdomains" into "macrodomains" also play an important role in the spatiotemporal organization of plasma membrane-associated processes taking place in lipid rafts .
In addition to lipid domains, cells have other means by which they can control the formation and maintenance of specific assemblies of membrane proteins (for reviews, see [3,5,11,30]). Protein-protein interactions - for example, between the transmembrane a-helices - may also contribute to the stability of protein clusters and membrane microdomains . Vesicular transport mechanisms can produce selective accumulation of membrane proteins by means of "directed" transport of vesicular components to a given membrane region [32,33]. The cytoskeleton may act either by actively directing redistribution of proteins in the plasma membrane, or by restricting their motion and trapping them in a given membrane area by barriers formed from joint structures of the membrane and the cytoskeleton . The assembly of lipid rafts into macrodomains is also governed by the actin cytoskeleton (see  and references therein). The free diffusion of membrane proteins can also be hindered by interaction with elements of different cytosolic signaling elements (e.g., G-proteins, kinases). These factors are not independent of each other and may act in concert to generate supramolecular structures in the plasma membrane.
In this chapter selected examples for the existence of hierarchically built protein complexes are provided. Their regulation by the lipid domain structure of the plasma membrane and the functional consequences of the formation of protein clusters in transmembrane signaling will also be discussed.
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