Abstract
Caveolin-1 is the principle membrane protein of caveolae and plays an important role in various cellular processes. The protein contains two helices (H1 and H2) connected by a three-residue break. Although caveolin-1 is assumed to adopt a U-shaped conformation in the transmembrane domain, with both the N-terminus and C-terminus exposed to the cytoplasm, the structure and dynamics of caveolin-1 in membranes are still unclear. Here, we performed six molecular dynamics simulations to characterize the structure and dynamics of caveolin-1 (residues D82–S136; Cav182–136) in a caveolae-mimicking asymmetric lipid bilayer. The simulations reveal that the structure of the caveolin scaffolding domain of caveolin-1 is dynamic, as it could be either fully helical or partly unstructured. Cav182–136 inserts into the inner leaflet of the asymmetric lipid bilayer with a stable U-shaped conformation and orients almost vertical to the bilayer surface. The simulations also provide new insights into the effects of caveolin-1 on the morphology of caveolae and the possible interacting site of cholesterol on caveolin-1.
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References
Aoki S, Thomas A, Decaffmeyer M, Brasseur R, Epand RM (2010) The role of proline in the membrane re-entrant helix of caveolin-1. J Biol Chem 285:33371–33380. doi:10.1074/jbc.M110.153569
Berendsen HJ, Postma JPM, van Gunsteren WF, DiNola A, Haak J (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684–3690
Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126:014101
Couet J, Li S, Okamoto T, Ikezu T, Lisanti MP (1997) Identification of peptide and protein ligands for the caveolin-scaffolding domain: implications for the interaction of caveolin with caveolae-associated proteins. J Biol Chem 272:6525–6533. doi:10.1074/jbc.272.10.6525
Das K, Lewis RY, Scherer PE, Lisanti MP (1999) The membrane-spanning domains of caveolins-1 and -2 mediate the formation of caveolin hetero-oligomers: implications for the assembly of caveolae membranes in vivo. J Biol Chem 274:18721–18728. doi:10.1074/jbc.274.26.18721
Drab M et al (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293:2449–2452. doi:10.1126/science.1062688
Epand RM, Sayer BG, Epand RF (2005) Caveolin scaffolding region and cholesterol-rich domains in membranes. J Mol Biol 345:339–350. doi:10.1016/j.jmb.2004.10.064
Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593
Fernandez I, Ying Y, Albanesi J, Anderson RG (2002) Mechanism of caveolin filament assembly. Proc Natl Acad Sci USA 99:11193–11198. doi:10.1073/pnas.172196599
Gabella G (1976) Quantitative morphological study of smooth muscle cells of the guinea-pig taenia coli. Cell Tissue Res 170:161–186. doi:10.1007/BF00224297
Gratton JP, Bernatchez P, Sessa WC (2004) Caveolae and caveolins in the cardiovascular system. Circ Res 94:1408–1417. doi:10.1161/01.RES.0000129178.56294.17
Gri G, Molon B, Manes S, Pozzan T, Viola A (2004) The inner side of T cell lipid rafts. Immunol Lett 94:247–252. doi:10.1016/j.imlet.2004.05.012
Gupta R, Toufaily C, Annabi B (2014) Caveolin and cavin family members: dual roles in cancer. Biochimie 107(Pt B):188–202. doi:10.1016/j.biochi.2014.09.010
Hastings WR (1995) Caveolin is palmitoylated on multiple cysteine residues. J Biol Chem 270:6838–6842. doi:10.1074/jbc.270.12.6838
Hess B, Bekker H, Berendsen HJ, Fraaije JG (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18:1463–1472
Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4:435–447. doi:10.1021/Ct700301q
Hoop CL, Sivanandam VN, Kodali R, Srnec MN, van der Wel PCA (2012) Structural characterization of the caveolin scaffolding domain in association with cholesterol-rich membranes. Biochemistry 51:90–99. doi:10.1021/bi201356v
Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38
Ikonen E, Heino S, Lusa S (2004) Caveolins and membrane cholesterol. Biochem Soc Trans 32:121–123
Jansen M et al (2008) Cholesterol substitution increases the structural heterogeneity of caveolae. J Biol Chem 283:14610–14618. doi:10.1074/jbc.M710355200
Kandasamy SK, Larson RG (2006) Molecular dynamics simulations of model trans-membrane peptides in lipid bilayers: a systematic investigation of hydrophobic mismatch. Biophys J 90:2326–2343. doi:10.1529/biophysj.105.073395
Klauda JB et al (2010) Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J Phys Chem B 114:7830–7843. doi:10.1021/jp101759q
Le Lan C, Neumann JM, Jamin N (2006) Role of the membrane interface on the conformation of the caveolin scaffolding domain: a CD and NMR study. FEBS Lett 580:5301–5305. doi:10.1016/j.febslet.2006.08.075
Lee J, Glover KJ (2012) The transmembrane domain of caveolin-1 exhibits a helix-break-helix structure. Biochim Biophys Acta 1818:1158–1164. doi:10.1016/j.bbamem.2011.12.033
Liang X, Zu Y, Cao Y-P, Yang C (2013) A dual-scale model for the caveolin-mediated vesiculation. Soft Matter 9:7981. doi:10.1039/c3sm50956g
Lim JB, Rogaski B, Klauda JB (2012) Update of the cholesterol force field parameters in CHARMM. J Phys Chem B 116:203–210. doi:10.1021/jp207925m
Liu P, Rudick M, Anderson RG (2002) Multiple functions of caveolin-1. J Biol Chem 277:41295–41298. doi:10.1074/jbc.R200020200
Miyamoto S, Kollman PA (1992) Settle: an analytical version of the SHAKE and RATTLE algorithm for rigid water models. J Comput Chem 13:952–962. doi:10.1002/jcc.540130805
Mobley BA (1975) Sizes of components in frog skeletal muscle measured by methods of stereology. J Gen Physiol 66:31–45. doi:10.1085/jgp.66.1.31
Monier S, Parton RG, Vogel F, Behlke J, Henske A, Kurzchalia TV (1995) VIP21–caveolin, a membrane protein constituent of the caveolar coat, oligomerizes in vivo and in vitro. Mol Biol Cell 6:911–927. doi:10.1091/mbc.6.7.911
Murata M, Peränen J, Schreiner R, Wieland F, Kurzchalia TV, Simons K (1995) VIP21/caveolin is a cholesterol-binding protein. Proc Natl Acad Sci 92:10339–10343
Napolitano L (1963) The differentiation of white adipose cells. An electron microscope study. J Cell Biol 18:663–679. doi:10.1083/jcb.18.3.663
Parton RG, Hanzal-Bayer M, Hancock JF (2006) Biogenesis of caveolae: a structural model for caveolin-induced domain formation. J Cell Sci 119:787–796. doi:10.1242/jcs.02853
Pelkmans L, Zerial M (2005) Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae. Nature 436:128–133. doi:10.1038/nature03866
Pilch PF, Meshulam T, Ding S, Liu L (2011) Caveolae and lipid trafficking in adipocytes. Clin Lipidol 6:49–58. doi:10.2217/clp.10.80
Razani B, Woodman SE, Lisanti MP (2002) Caveolae: from cell biology to animal physiology. Pharmacol Rev 54:431–467. doi:10.1124/pr.54.3.431
Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, Anderson RG (1992) Caveolin, a protein component of caveolae membrane coats. Cell 68:673–682. doi:10.1016/0092-8674(92)90143-Z
Rui H, Root KT, Lee J, Glover KJ, Im W (2014) Probing the U-shaped conformation of caveolin-1 in a bilayer. Biophys J 106:1371–1380. doi:10.1016/j.bpj.2014.02.005
Schlegel A, Lisanti MP (2000) A molecular dissection of caveolin-1 membrane attachment and oligomerization. Two separate regions of the caveolin-1 C-terminal domain mediate membrane binding and oligomer/oligomer interactions in vivo. J Biol Chem 275:21605–21617. doi:10.1074/jbc.M002558200
Schlegel A, Schwab RB, Scherer PE, Lisanti MP (1999) A role for the caveolin scaffolding domain in mediating the membrane attachment of caveolin-1: the caveolin scaffolding domain is both necessary and sufficient for membrane binding in vitro. J Biol Chem 274:22660–22667. doi:10.1074/jbc.274.32.22660
Sengupta D (2012) Cholesterol modulates the structure, binding modes, and energetics of caveolin–membrane interactions. J Phys Chem B 116:14556–14564. doi:10.1021/jp3077886
Serra M, Scotlandi K (2009) Caveolins in the development and diseases of musculoskeletal system. Cancer Lett 284:113–121. doi:10.1016/j.canlet.2009.02.016
Shaul PW, Anderson RG (1998) Role of plasmalemmal caveolae in signal transduction. Am J Physiol 275:L843–L851
Simons K, Sampaio JL (2011) Membrane organization and lipid rafts. Cold Spring Harb Perspect Biol 3:a004697
Simons K, Vaz WL (2004) Model systems, lipid rafts, and cell membranes. Annu Rev Biophys Biomol Struct 33:269–295. doi:10.1146/annurev.biophys.32.110601.141803
Smart EJ, Anderson RGW (2002) Alterations in membrane cholesterol that affect structure and function of caveolae. Methods Enzymol 353:131–139. doi:10.1016/s0076-6879(02)53043-3
Smart EJ et al (1999) Caveolins, liquid-ordered domains, and signal transduction. Mol Cell Biol 19:7289–7304
Song KS, Tang Z, Li S, Lisanti MP (1997) Mutational analysis of the properties of caveolin-1: a novel role for the C-terminal domain in mediating homo-typic caveolin–caveolin interactions. J Biol Chem 272:4398–4403. doi:10.1074/jbc.272.7.4398
Sowmya BL, Jagannadham MV, Nagaraj R (2006) Interaction of synthetic peptides corresponding to the scaffolding domain of caveolin-3 with model membranes. Biopolymers 84:615–624. doi:10.1002/bip.20595
Spisni E, Tomasi V, Cestaro A, Tosatto SC (2005) Structural insights into the function of human caveolin 1. Biochem Biophys Res Commun 338:1383–1390. doi:10.1016/j.bbrc.2005.10.099
Thomas CM, Smart EJ (2008) Caveolae structure and function. J Cell Mol Med 12:796–809. doi:10.1111/j.1582-4934.2008.00295.x
Venable RM, Sodt AJ, Rogaski B, Rui H, Hatcher E, MacKerell AD Jr, Pastor RW, Klauda JB (2014) CHARMM all-atom additive force field for sphingomyelin: elucidation of hydrogen bonding and of positive curvature. Biophys J 107:134–145. doi:10.1016/j.bpj.2014.05.034
Yamada E (1955) The fine structure of the gall bladder epithelium of the mouse. J Cell Biol 1:445–458. doi:10.1083/jcb.1.5.445
Yang G, Xu H, Li Z, Li F (2014) Interactions of caveolin-1 scaffolding and intramembrane regions containing a CRAC motif with cholesterol in lipid bilayers. Biochim Biophys Acta 1838:2588–2599. doi:10.1016/j.bbamem.2014.06.018
Yang G, Dong Z, Xu H, Wang C, Li H, Li Z, Li F (2015) Structural study of caveolin-1 intramembrane domain by circular dichroism and nuclear magnetic resonance. Biopolymers 104:11–20. doi:10.1002/bip.22597
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Grant Numbers 21422208, 81173027, 81230076 and 21210003), the Hi-Tech Research and Development Program of China (Grant Numbers 2012AA020302 and 2012AA01A305), and the SA-SIBS Scholarship Program. We thank the National Supercomputing Center in Tianjin (Tianhe) and the National Supercomputing Center in Jinan for computational resources.
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Liu, H., Yang, L., Zhang, Q. et al. Probing the structure and dynamics of caveolin-1 in a caveolae-mimicking asymmetric lipid bilayer model. Eur Biophys J 45, 511–521 (2016). https://doi.org/10.1007/s00249-016-1118-1
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DOI: https://doi.org/10.1007/s00249-016-1118-1