Tetraspanins as master organizers of the plasma membrane

Inspired by the fluid mosaic cell membrane model of Singer and Nicolson,¹ cell biologists have extensively investigated the biochemical and biophysical properties of the plasma membrane in the last decades. The identification of separate compartments in the cell membrane that are enriched in specific proteins and lipids has been a major advance in membrane science.^2,3 This principle, referred to as membrane compartmentalization, is essential for efficient transmission of extracellular stimuli into intracellular signals. Different types of membrane compartments (also called microdomains or nanodomains) have been characterized on the basis of their different protein–lipid composition, size, and biophysical behavior. Classical lipid nanodomains (rafts) are dependent on strong interactions between cholesterol and sphingolipids, which can sequester specific signaling proteins, allowing for the formation of large signaling assemblies.⁴ In the “picket fence” model, transmembrane proteins and phospholipids can undergo hop diffusion between membrane compartments, whereas they can move freely within a compartment formed by the actin-based membrane skeleton.⁵ This chapter focuses on the biological functions and molecular mechanisms of tetraspanin-enriched microdomains (TEMs), with the goal of presenting a unifying concept for tetraspanin function in the plasma membrane.