Unraveling the architecture of caveolae

The eukaryotic cell surface is composed of many distinct membrane domains that are formed by the cooperative interactions of different proteins and lipids. These domains are important for membrane trafficking and cell signaling and are modulated in turn by changes in the cell environment. Caveolae (“little caves”) are ∼60-nm membrane invaginations (Fig. 1) that are a dominant surface feature of many mammalian cells, including muscle fibers, endothelia, and adipocytes, where they play a role in membrane homeostasis, signaling, and cellular mechanoprotection. Formation of caveolae in vertebrate cells requires two distinct protein families: the membrane-embedded caveolins (CAV1–3) and the peripheral membrane cavins (Cavin1–4). Although the general morphology of caveolae has been known for decades, the atypical structures of the protein subunits has meant that progress has been slow with regards to the high-resolution studies of caveola architecture. By high-resolution scanning electron microscopy (EM) and frozen deep-etch transmission EM, caveolae have been shown to be coated with striations (1, 2) or to possess spike-like structures (3), very different from other well-characterized vesicle coats, such as clathrin (4, 5). In PNAS, Stoeber et al. use a combination of biochemical dissection and EM to provide important insights into the underlying architecture of the caveola protein coat (6). Proposed model for the assembly of caveolae. (A) Electron micrograph of caveolae in an adipocyte cell line. (Scale bar, 100 nm.) (B) Schematic diagrams depicting the main features of the CAV1 and Cavin1 proteins required for caveola formation. Cavins possess two regions of α-helical structure, termed HR1 and HR2, which are rich in basic residues. These are linked by disordered acidic sequences DR1–DR3. Caveolins are membrane-integral proteins that are embedded by a central helix–turn–helix. They also possess a conserved sequence suggested to be involved in oligomerization (oligomerization domain, OD) and a sequence with potential …