8.A.26 The Caveolin (Caveolin) Family

Caveolin-1 is the primary structural protein of caveolae, small plasma membrane invaginations that are involved in transcytosis, cholesterol transport, signal transduction and cancer (Quest et al., 2008). It regulates endothelial permeability and therefore controls transport of fluids and solutes across semi-permeable vascular endothelial barriers (Minshall and Malik, 2006; Sun et al., 2011). It regulated both the transcellular and paracellular pathways, and controls vesicle trafficking including localization of signalling molecules that mediate vesicle fission, endocytosis, fusion and exocytosis (Minshall and Malik, 2006). Cholesterol efflux from lipid-loaded cells is also regulated by calveolin-1 via a 'caveolae transport center', an intracellular trafficking system of the caveolin-1 complex, and transmembrane transport systems of the ABC-A1 (TC#3.A.1.211.1) and SR-B1 complexes. Both ABC transporters transfer cholesterol from caveolae to extracellular HDL/ApoA1 (Luo et al., 2010). A proline in the integral membrane reentrant helix of caveolin-1 controls the topology of the protein (Aoki et al., 2010).  Caveolins interact directly with several Kv1 channels such as Kv1.3 (1.A.1.2.4) to influence their activities and promote associations with lipid rafts (Pérez-Verdaguer et al. 2016).  Cav-1, Cav-2 and Cavin-1 may be reliable markers for identification of liposarcoma tumors characterized by consistent adipogenic differentiation (Codenotti et al. 2016).

Progesterone and its polar metabolites trigger meiotic division in the amphibian oocyte through a non-genomic signaling system at the plasma membrane. Site-directed mutagenesis studies of ouabain binding and progesterone-ouabain competition indicated that Progesterone binds to a 23 amino acid extracellular loop of the plasma membrane α-subunit of the Na/K-ATPase. Integral membrane proteins such as caveolins are reported to form Na/K-ATPase-peptide complexes essential for signal transduction. Morrill et al. (2012) characterized the progesterone-induced Na/K-ATPase-caveolin (CAV-1)-steroid 5α-reductase interactions initiating meiotic division. Peptide sequence analysis algorithms indicated that CAV-1 contains two plasma membrane spanning helices separated by as few as 1-2 amino acid residues at the cell surface. The CAV-1 scaffolding domain, reported to interact with CAV-1 binding (CB) motifs in signaling proteins, overlaps TMS1. The α-subunits of Na/K-ATPases (10 TMSs) contain double CB motifs within TMS1 and TMS10. Steroid 5α-reductase (6 TMSs), an initial step in polar steroid formation, contains CB motifs overlapping TMSs 1 and 6. Computer analyses predicted that interaction between antipathic strands may bring CB motifs and scaffolding domains into close proximity, initiating allostearic changes. Progesterone binding to the α-subunit may thus facilitate CB motif:CAV-1 interactions, which in turn induce helix-helix interaction and generate both a signaling cascade and formation of polar steroids.

Caveolae, 50-100 nm invaginations found within the plasma membranes of cells, are involved in processes that are essential for homeostasis, most notably endocytosis, mechano-protection, and signal transduction. Caveolins participate in these processes, but are structural proteins responsible for caveolae biogenesis. When caveolin is misregulated or mutated, disease states can arise (e.g., muscular dystrophy, cancers, and heart disease. Caveolin does not have a transmembrane orientation; instead, it adopts a topography where both the N- and C-termini lie on the cytoplasmic side of the membrane, and the hydrophobic span adopts an intramembrane loop. Structural information has been integrated into a model of the caveolin secondary structure (Root et al. 2019).

Neural tube closure (NTC) is a complex multi-step morphogenetic process that transforms the flat neural plate found on the surface of the neurula embryo into the hollow and subsurface central nervous system (CNS). Errors in this process underlie some of the most prevalent human birth defects, and occur in about 1 out of every 1000 births. A mutant in the basal chordate Ciona savignyi (named bugeye) revealed a novel role for a T-type calcium channel (Cav3) in this process (Smith et al. 2021). Loss of CAV3 leads to defects restricted to anterior NTC, with the brain apparently fully developed, but protruding from the head (Smith et al. 2021).

Transmembrane proteins are internalized by clathrin- and caveolin-dependent endocytosis. Both pathways converge on early endosomes and are thought to share the small GTPase Rab5 as a common regulator. In contrast to this notion, Shikanai et al. 2023 showed that the clathrin- and caveolin-mediated endocytic pathways are differentially regulated. Rab5 and Rab21 localize to distinct populations of early endosomes in cortical neurons and preferentially regulate clathrin- and caveolin-mediated pathways, respectively, suggesting heterogeneity in the early endosomes, rather than a converging point. Suppression of Rab21, but not Rab5, results in decreased plasma membrane localization and total protein levels of caveolin-1, which perturbs immature neurite pruning of cortical neurons, an in vivo-specific step of neuronal maturation. Thus, clathrin- and caveolin-mediated endocytic pathways run in parallel in early endosomes, which show different molecular regulation and physiological function (Shikanai et al. 2023).