Unraveling the architecture of caveolae

Abstract

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 deepetch 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).The first protein component of caveolae to be identified and shown to be essential for caveola formation was CAV1 (7-9). Subsequently, it was found that both CAV2 and muscle-specific CAV3 homologs are also localized to caveolae. Caveolin proteins are ∼20 kDa and possess two membrane-inserted α-helices with cytoplasmic N-and C-terminal sequences. These proteins form oligomeric complexes at the plasma membrane that line the cytoplasmic leaflet of the invaginated caveola structures. Cavins, although equally important for caveola formation, were only identified in the past decade through proteomic and cellular studies from several groups. Cavins also possess a conserved and unique structural organization, in this case consisting of conserved N-and C-terminal α-helical domains (HR1 and HR2) interspersed by disordered linker sequences (DR1, DR2, DR3) (10). Although recent studies have begun to tease out the functions of these domains in membrane recruitment, remodeling, and protein-protein interactions, our understanding is still limited. For example, how do caveolin oligomers assemble within caveolae, and what drives cavin oligomerization and recruitment to caveolar domains at the cell surface?In their report, Stoeber et al. (6) propose a model for the arrangement of the caveolin and cavin proteins that begins to address some of the ongoing questions in the field. Affinity purification of Cavin1 expressed in HEK293 cells revealed the presence of heterogeneous particles with a mesh-like appearance by cryoEM and 3D electron tomography. These particles bound robustly to liposomes containing phosphatidylserine (PS) or phosphatidic acid, as...

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