According to our present knowledge, lateral arrangement of membrane components - whether proteins or lipids - is a general phenomenon, which is essential for the proper functioning of both the individual molecules and the whole of the plasma membrane. Processes associated with the plasma membrane (e.g., signal transduction, protein sorting, etc.) demand the cooperation of various membrane proteins and are often accompanied by dynamic rearrangement of the two-dimensional macromolecular patterns at the cell surface. The structured, and at the same time dynamic, nature of the plasma membrane allows accumulation of relevant molecules in particular membrane areas whilst excluding others, thus preventing their interaction [9-11].
The basic organization level of membrane proteins is defined by their molecular association/physical proximity, and is referred to as nanometer- or small-scale clusters . These clusters can be formed either in a homologous or heterologous fashion; that is, their molecular components can be either identical or distinct. The generalized occurrence of such protein complexes was initially proposed in the early 1980s, based on the preferential accommodation of the genetically determined membrane-spanning a-helices of proteins into distinct membrane microdomains . This assumption has been supported by a considerable amount of experimental data. A major asset in studying small-scale protein assemblies was the adaptation of fluorescence resonance energy transfer (FRET) to cellular systems (see Section 7.2).
Different types of small-scale protein patterns can be distinguished in the plasma membrane :
• In many cases, a given "functional unit" comprises several components/sub-units (e.g., in multi-chain immune recognition receptor complexes ).
• External stimuli can also induce cluster formation through reorganization of membrane proteins in the plane of the plasma membrane (e.g., ligand-evoked aggregation of the epidermal growth factor receptor ).
• Apart from the aforesaid examples, where the individual components are either preassembled or come together upon ligand binding/external stimuli, co-localization of apparently unrelated proteins can also be observed in many cases (e. g., association of the insulin receptor and major histocompatability complex (MHC) I glycoproteins [15,16]). Revealing the co-localization of such proteins may call our attention to their potential functional relationship.
Beyond the small-scale protein associations (i.e., colocalization on the 1- to 10-nm scale), clustering of membrane proteins at a second hierarchical level can also be observed in many cases [5,11,17]. These so-called large-scale clusters can be several hundred nanometers in diameter and could contain tens to thousands of proteins. Some of the biophysical methods applicable for studying large-scale protein clusters are summarized in Section 7.2.
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