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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).

References associated with 8.A.26 family:

Codenotti, S., M. Vezzoli, P.L. Poliani, M. Cominelli, F. Bono, H. Kabbout, F. Faggi, N. Chiarelli, M. Colombi, I. Zanella, G. Biasiotto, A. Montanelli, L. Caimi, E. Monti, and A. Fanzani. (2016). Caveolin-1, Caveolin-2 and Cavin-1 are strong predictors of adipogenic differentiation in human tumors and cell lines of liposarcoma. Eur J. Cell Biol. [Epub: Ahead of Print] 27168348
Li, X., F. Yao, W. Zhang, C. Cheng, B. Chu, Y. Liu, Y. Mei, Y. Wu, X. Zou, and L. Hou. (2014). Identification, expression pattern, cellular location and potential role of the caveolin-1 gene from Artemia sinica. Gene 540: 161-170. 24583171
Meshulam, T., J.R. Simard, J. Wharton, J.A. Hamilton, and P.F. Pilch. (2006). Role of caveolin-1 and cholesterol in transmembrane fatty acid movement. Biochemistry 45: 2882-2893. 16503643
Morrill GA., Kostellow AB. and Askari A. (2012). Caveolin-Na/K-ATPase interactions: role of transmembrane topology in non-genomic steroid signal transduction. Steroids. 77(11):1160-8. 22579740
Pérez-Verdaguer, M., J. Capera, R. Martínez-Mármol, M. Camps, N. Comes, M.M. Tamkun, and A. Felipe. (2016). Caveolin interaction governs Kv1.3 lipid raft targeting. Sci Rep 6: 22453. 26931497
Root, K.T., J.A. Julien, and K.J. Glover. (2019). Secondary structure of caveolins: a mini review. Biochem Soc Trans. [Epub: Ahead of Print] 31551358
Shin, J., Y.H. Jung, D.H. Cho, M. Park, K.E. Lee, Y. Yang, C. Jeong, B.H. Sung, J.H. Sohn, J.B. Park, and D.H. Kweon. (2015). Display of membrane proteins on the heterologous caveolae carved by caveolin-1 in the Escherichia coli cytoplasm. Enzyme Microb Technol 79-80: 55-62. 26320715
Smith, H.M., S.M. Khairallah, A.H. Nguyen, E. Newman-Smith, and W.C. Smith. (2021). Misregulation of cell adhesion molecules in the Ciona neural tube closure mutant bugeye. Dev Biol 480: 14-24. [Epub: Ahead of Print] 34407458
Udayantha, H.M.V., S.D.N.K. Bathige, T.T. Priyathilaka, S. Lee, M.J. Kim, and J. Lee. (2017). Identification and characterization of molluscan caveolin-1 ortholog from Haliotis discus discus: Possible involvement in embryogenesis and host defense mechanism against pathogenic stress. Gene Expr Patterns 27: 85-92. [Epub: Ahead of Print] 29128397