Different physical properties of lipids and proteins allow them to localize and form distinct islands or domains in the membrane. Some membrane domains are formed due to protein-protein interactions, whereas others are formed due to the presence of specific lipids such as sphingolipids and sterols—for example, large proteins, such as bacteriorhodopsin, aggregate and create distinct domains.

Another mechanism for membrane domain formation involves membrane proteins interacting with cytoskeletal or exoplasmic proteins. For example, spectrin, the cytoskeletal protein found in red blood cells, directly interacts with integral membrane proteins and immobilizes them. The inner layer of a plasma membrane closely associated with the protein cytoskeleton network forms distinct compartments or corrals. The movement of proteins presents within the corrals is often restricted by the fence of the corrals. Such restrictions prevent the lateral diffusion of the proteins and result in the formation of the protein domains.

Proteins involved in cell-cell interactions bind to the proteins from neighboring cells. These interactions between the two cell surfaces lock the membrane proteins in place and result in the formation of protein domains. For example, tight junctions are membrane microdomains that form a watertight seal between two adjacent animal cells. Predominantly two proteins, claudins and occludins, tightly hold the cells against each other. Apart from that, in animal cells, desmosomes are another highly ordered membrane domains that act like spot welds between adjacent epithelial cells. Cadherins, short proteins in the plasma membrane, connect to intermediate filaments via linker proteins like desmoplakin, plakoglobin, and plakophilin to create desmosomes. The cadherins connect two adjacent cells and maintain the cells in a sheet-like formation in organs and tissues that stretch, like the skin, heart, and muscles.

Some part of this text is adapted from Openstax, Biology 2e, 4.6 Connections between Cells and Cellular Activities