Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics

Journal of General Physiology

Volumn 138, Issue 5, 2011, Pages 475-493

  Kwon, Taekyung ^a   Harris, Andrew L ^b   Rossi, Angelo ^b   Bargiello, Thaddeus A ^a  

^a ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^b RUTGERS NEW JERSEY MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CONNEXIN 26; GAP JUNCTION PROTEIN;

ANIMAL; ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; CRYSTALLIZATION; GENE EXPRESSION REGULATION; HUMAN; METABOLISM; MOLECULAR DYNAMICS; MONTE CARLO METHOD; OOCYTE; PHYSIOLOGY; PROTEIN CONFORMATION; XENOPUS;

ANIMALS; CONNEXINS; CRYSTALLIZATION; GENE EXPRESSION REGULATION; HUMANS; MODELS, MOLECULAR; MOLECULAR DYNAMICS SIMULATION; MONTE CARLO METHOD; OOCYTES; PROTEIN CONFORMATION; XENOPUS;

EID: 80555135976     PISSN: 00221295     EISSN: 15407748     Source Type: Journal    
DOI: 10.1085/jgp.201110679     Document Type: Article

References (92)

1. Allen, M.J., J. Gemel, E.C. Beyer, and R. Lal. 2011. Atomic force microscopy of Connexin40 gap junction hemichannels reveals calcium-dependent three-dimensional molecular topography and open-closed conformations of both the extracellular and cytoplasmic faces. J. Biol. Chem. 286:22139-22146. http://dx.doi.org/10.1074/jbc.M111.240002
2. Arnesen, T. 2011. Towards a functional understanding of protein N-terminal acetylation. PLoS Biol. 9:e1001074. http://dx.doi.org/10.1371/journal.pbio.1001074
3. Arnesen, T., P. Van Damme, B. Polevoda, K. Helsens, R. Evjenth, N. Colaert, J.E. Varhaug, J. Vandekerckhove, J.R. Lillehaug, F. Sherman, and K. Gevaert. 2009. Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans. Proc. Natl. Acad. Sci. USA. 106:8157-8162. http://dx.doi.org/10.1073/pnas.0901931106
4. Bargiello, T., and P. Brink. 2009. Voltage-gating mechanisms of connexin channels. In Connexins. A.L. Harris and D. Locke, editors. Humana Press, New York. 103-128.
5. Bas, D.C., D.M. Rogers, and J.H. Jensen. 2008. Very fast prediction and rationalization of pKa values for protein-ligand complexes. Proteins. 73:765-783. http://dx.doi.org/10.1002/prot.22102
6. Basu, A., K.L. Rose, J. Zhang, R.C. Beavis, B. Ueberheide, B.A. Garcia, B. Chait, Y. Zhao, D.F. Hunt, E. Segal, et al. 2009. Proteome-wide prediction of acetylation substrates. Proc. Natl. Acad. Sci. USA. 106:13785-13790. http://dx.doi.org/10.1073/pnas.0906801106
7. Berns, A.J.M., M. van Kraaikamp, H. Bloemendal, and C.D. Lane. 1972. Calf crystallin synthesis in frog cells: the translation of lenscell 14S RNA in oocytes. Proc. Natl. Acad. Sci. USA. 69:1606-1609. http://dx.doi.org/10.1073/pnas.69.6.1606
8. Beyer, E.C., and V.M. Berthoud. 2009. The family of connexin genes. In Connexins. A.L. Harris and D. Locke, editors. Humana Press, New York. 3-26.
9. Bradshaw, R.A., W.W. Brickey, and K.W. Walker. 1998. N-terminal processing: the methionine aminopeptidase and N alpha-acetyl transferase families. Trends Biochem. Sci. 23:263-267. http://dx.doi.org/10.1016/S0968-0004(98)01227-4
10. Brooks, B.R., R.E. Bruccoleri, B.D. Olafson, D.J. States, S. Swaminathan, and M. Karplus. 1983. CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J. Comput. Chem. 4:187-217. http://dx.doi.org/10.1002/jcc.540040211
11. Brooks, B.R., C.L. Brooks III, A.D. Mackerell Jr., L. Nilsson, R.J. Petrella, B. Roux, Y. Won, G. Archontis, C. Bartels, S. Boresch, et al. 2009. CHARMM: The biomolecular simulation program. J. Comput. Chem. 30:1545-1614. http://dx.doi.org/10.1002/jcc.21287
12. Brown, M.A., G.S. Begley, E. Czerwiec, L.M. Stenberg, M. Jacobs, D.E. Kalume, P. Roepstorff, J. Stenflo, B.C. Furie, and B. Furie. 2005. Precursors of novel Gla-containing conotoxins contain a carboxyterminal recognition site that directs ?-carboxylation. Biochemistry. 44:9150-9159. http://dx.doi.org/10.1021/bi0503293
13. Buck, M., S. Bouguet-Bonnet, R.W. Pastor, and A.D. MacKerell Jr. 2006. Importance of the CMAP correction to the CHARMM22 protein force field: dynamics of hen lysozyme. Biophys. J. 90: L36-L38. http://dx.doi.org/10.1529/biophysj.105.078154
14. Buffy, J.J., M.J. McCormick, S. Wi, A. Waring, R.I. Lehrer, and M. Hong. 2004. Solid-state NMR investigation of the selective perturbation of lipid bilayers by the cyclic antimicrobial peptide RTD-1. Biochemistry. 43:9800-9812. http://dx.doi.org/10.1021/bi036243w
15. Caves, L.S., J.D. Evanseck, and M. Karplus. 1998. Locally accessible conformations of proteins: multiple molecular dynamics simulations of crambin. Protein Sci. 7:649-666.
16. Chang, Q., W. Tang, S. Ahmad, B. Zhou, and X. Lin. 2008. Gap junction mediated intercellular metabolite transfer in the cochlea is compromised in connexin30 null mice. PLoS ONE. 3:e4088. http://dx.doi.org/10.1371/journal.pone.0004088
17. Choudhary, C., C. Kumar, F. Gnad, M.L. Nielsen, M. Rehman, T.C. Walther, J.V. Olsen, and M. Mann. 2009. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 325:834-840. http://dx.doi.org/10.1126/science.1175371
18. Drag, M., M. Bogyo, J.A. Ellman, and G.S. Salvesen. 2010. Aminopeptidase fingerprints, an integrated approach for identification of good substrates and optimal inhibitors. J. Biol. Chem. 285:3310-3318. http://dx.doi.org/10.1074/jbc.M109.060418
19. Egwolf, B., Y. Luo, D.E. Walters, and B. Roux. 2010. Ion selectivity of alpha-hemolysin with beta-cyclodextrin adapter. II. Multiion effects studied with grand canonical Monte Carlo/Brownian dynamics simulations. J. Phys. Chem. B. 114:2901-2909. http://dx.doi.org/10.1021/jp906791b
20. Essmann, U., L. Perera, M.L. Berkowitz, T. Darden, H. Lee, and L.G. Pedersen. 1995. A smooth particle mesh Ewald method. J. Chem. Phys. 103:8577-8593. http://dx.doi.org/10.1063/1.470117
21. Feller, S.E., and A.D. MacKerell. 2000. An improved empirical potential energy function for molecular simulations of phospholipids. J. Phys. Chem. B. 104:7510-7515. http://dx.doi.org/10.1021/jp0007843
22. Fleishman, S.J., V.M. Unger, M. Yeager, and N. Ben-Tal. 2004. A Calpha model for the transmembrane alpha helices of gap junction intercellular channels. Mol. Cell. 15:879-888. http://dx.doi.org/10.1016/j.molcel.2004.08.016
23. Forte, G.M.A., M.R. Pool, and C.J. Stirling. 2011. N-terminal acetylation inhibits protein targeting to the endoplasmic reticulum. PLoS Biol. 9:e1001073. http://dx.doi.org/10.1371/journal.pbio.1001073
24. Frottin, F., A. Martinez, P. Peynot, S. Mitra, R.C. Holz, C. Giglione, and T. Meinnel. 2006. The proteomics of N-terminal methionine cleavage. Mol. Cell. Proteomics. 5:2336-2349. http://dx.doi.org/10.1074/mcp.M600225-MCP200
25. Furie, B., B.A. Bouchard, and B.C. Furie. 1999. Vitamin K-dependent biosynthesis of γ-carboxyglutamic acid. Blood. 93:1798-1808.
26. Goetze, S., E. Qeli, C. Mosimann, A. Staes, B. Gerrits, B. Roschitzki, S. Mohanty, E.M. Niederer, E. Laczko, E. Timmerman, et al. 2009. Identification and functional characterization of N-terminally acetylated proteins in Drosophila melanogaster. PLoS Biol. 7: e1000236. http://dx.doi.org/10.1371/journal.pbio.1000236
27. Gong, X.Q., and B.J. Nicholson. 2001. Size selectivity between gap junction channels composed of different connexins. Cell Commun. Adhes. 8:187-192. http://dx.doi.org/10.3109/15419060109080721
28. González, D., J.M. Gómez-Hernández, and L.C. Barrio. 2006. Species specificity of mammalian connexin-26 to form open voltage-gated hemichannels. FASEB J. 20:2329-2338. http://dx.doi.org/10.1096/fj.06-5828com
29. Grossfield, A., S.E. Feller, and M.C. Pitman. 2007. Convergence of molecular dynamics simulations of membrane proteins. Proteins. 67:31-40. http://dx.doi.org/10.1002/prot.21308
30. Harris, A.L., and D. Locke. 2009. Permeability of connexin channels. In Connexins: A Guide. A.L. Harris and D. Locke, editors. Humana Press, New York. 165-206 pp.
31. Harris, A.L., D.C. Spray, and M.V. Bennett. 1981. Kinetic properties of a voltage-dependent junctional conductance. J. Gen. Physiol. 77:95-117. http://dx.doi.org/10.1085/jgp.77.1.95
32. Helbig, A.O., S. Gauci, R. Raijmakers, B. van Breukelen, M. Slijper, S. Mohammed, and A.J.R. Heck. 2010. Profiling of N-acetylated protein termini provides in-depth insights into the N-terminal nature of the proteome. Mol. Cell. Proteomics. 9:928-939. http://dx.doi.org/10.1074/mcp.M900463-MCP200
33. Hertzberg, E.L., R.M. Disher, A.A. Tiller, Y. Zhou, and R.G. Cook. 1988. Topology of the Mr 27,000 liver gap junction protein. Cytoplasmic localization of amino- and carboxyl termini and a hydrophilic domain which is protease-hypersensitive. J. Biol. Chem. 263:19105-19111.
34. Hoover, W.G. 1985. Canonical dynamics: equilibrium phase-space distributions. Phys. Rev. A. 31:1695-1697. http://dx.doi.org/10.1103/PhysRevA.31.1695
35. Hwang, C.S., A. Shemorry, and A. Varshavsky. 2010. N-terminal acetylation of cellular proteins creates specific degradation signals. Science. 327:973-977. http://dx.doi.org/10.1126/science.1183147
36. Im, W., and B. Roux. 2001. Brownian dynamics simulations of ions channels: a general treatment of electrostatic reaction fields for molecular pores of arbitrary geometry. J. Chem. Phys. 115:4850-4861. http://dx.doi.org/10.1063/1.1390507
37. Im, W., S. Seefeld, and B. Roux. 2000. A grand canonical Monte Carlo-Brownian dynamics algorithm for simulating ion channels. Biophys. J. 79:788-801. http://dx.doi.org/10.1016/S0006-3495(00)76336-3
38. Ingólfsson, H.I., Y. Li, V.V. Vostrikov, H. Gu, J.F. Hinton, R.E. Koeppe II, B. Roux, and O.S. Andersen. 2011. Gramicidin A backbone and side chain dynamics evaluated by molecular dynamics simulations and nuclear magnetic resonance experiments. I: molecular dynamics simulations. J. Phys. Chem. B. 115:7417-7426. http://dx.doi.org/10.1021/jp200904d
39. Ishida, T., and K. Kinoshita. 2007. PrDOS: prediction of disordered protein regions from amino acid sequence. Nucleic Acids Res. 35:W460-W464. http://dx.doi.org/10.1093/nar/gkm363
40. Jo, S., T. Kim, and W. Im. 2007. Automated builder and database of protein/membrane complexes for molecular dynamics simulations. PLoS ONE. 2:e880. http://dx.doi.org/10.1371/journal.pone.0000880
41. Jo, S., T. Kim, V.G. Iyer, and W. Im. 2008. CHARMM-GUI: a webbased graphical user interface for CHARMM. J. Comput. Chem. 29:1859-1865. http://dx.doi.org/10.1002/jcc.20945
42. Jo, S., J.B. Lim, J.B. Klauda, and W. Im. 2009. CHARMM-GUI Membrane Builder for mixed bilayers and its application to yeast membranes. Biophys. J. 97:50-58. http://dx.doi.org/10.1016/j.bpj.2009.04.013
43. Kalmatsky, B.D., S. Bhagan, Q. Tang, T.A. Bargiello, and T.L. Dowd. 2009. Structural studies of the N-terminus of Connexin 32 using 1H NMR spectroscopy. Arch. Biochem. Biophys. 490:9-16. http://dx.doi.org/10.1016/j.abb.2009.07.015
44. Karlin, A., and M.H. Akabas. 1998. Substituted-cysteine accessibility method. In Methods in Enzymology. P.M. Conn, editor. Academic Press, Waltham, MA. 123-145.
45. Kienker, P.K., and J.D. Lear. 1995. Charge selectivity of the designed uncharged peptide ion channel Ac-(LSSLLSL)3-CONH2. Biophys. J. 68:1347-1358. http://dx.doi.org/10.1016/S0006-3495(95)80307-3
46. Klauda, J.B., R.M. Venable, J.A. Freites, J.W. O'Connor, D.J. Tobias, C. Mondragon-Ramirez, I. Vorobyov, A.D. MacKerell Jr., and R.W. Pastor. 2010. Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J. Phys. Chem. B. 114:7830-7843. http://dx.doi.org/10.1021/jp101759q
47. Kronengold, J., E.B. Trexler, F.F. Bukauskas, T.A. Bargiello, and V.K. Verselis. 2003. Single-channel SCAM identifies pore-lining residues in the first extracellular loop and first transmembrane domains of Cx46 hemichannels. J. Gen. Physiol. 122:389-405. http://dx.doi.org/10.1085/jgp.200308861
48. Kucerka, N., J.D. Perlmutter, J. Pan, S. Tristram-Nagle, J. Katsaras, and J.N. Sachs. 2008. The effect of cholesterol on short- and long-chain monounsaturated lipid bilayers as determined by molecular dynamics simulations and X-ray scattering. Biophys. J. 95:2792-2805. http://dx.doi.org/10.1529/biophysj.107.122465
49. Lee, K.I., H. Rui, R.W. Pastor, and W. Im. 2011. Brownian dynamics simulations of ion transport through the VDAC. Biophys. J. 100:611-619. http://dx.doi.org/10.1016/j.bpj.2010.12.3708
50. Li, D.-W., S.A. Showalter, and R. Brüschweiler. 2010. Entropy localization in proteins. J. Phys. Chem. B. 114:16036-16044. http://dx.doi.org/10.1021/jp109908u
51. Li, H., A.D. Robertson, and J.H. Jensen. 2005. Very fast empirical prediction and rationalization of protein pKa values. Proteins. 61:704-721. http://dx.doi.org/10.1002/prot.20660
52. Liu, F., F.T. Arce, S. Ramachandran, and R. Lal. 2006. Nanomechanics of hemichannel conformations: connexin flexibility underlying channel opening and closing. J. Biol. Chem. 281:23207-23217. http://dx.doi.org/10.1074/jbc.M605048200
53. Locke, D., S. Bian, H. Li, and A.L. Harris. 2009. Post-translational modifications of connexin26 revealed by mass spectrometry. Biochem. J. 424:385-398. http://dx.doi.org/10.1042/BJ20091140
54. MacKerell, A.D., Jr., D. Bashford, M. Bellott, R.L. Dunbrack, J.D. Evanseck, M.J. Field, S. Fischer, J. Gao, H. Guo, S. Ha, et al. 1998. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B. 102:3586-3616. http://dx.doi.org/10.1021/jp973084f
55. Mackerell, A.D., Jr., M. Feig, and C.L. Brooks III. 2004. Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J. Comput. Chem. 25:1400-1415. http://dx.doi.org/10.1002/jcc.20065
56. Maeda, S., S. Nakagawa, M. Suga, E. Yamashita, A. Oshima, Y. Fujiyoshi, and T. Tsukihara. 2009. Structure of the connexin 26 gap junction channel at 3.5 Å resolution. Nature. 458:597-602. http://dx.doi.org/10.1038/nature07869
57. Müller, D.J., G.M. Hand, A. Engel, and G.E. Sosinsky. 2002. Conformational changes in surface structures of isolated connexin 26 gap junctions. EMBO J. 21:3598-3607. http://dx.doi.org/10.1093/emboj/cdf365
58. Nicholson, B.J., M.W. Hunkapiller, L.B. Grim, L.E. Hood, and J.P. Revel. 1981. Rat liver gap junction protein: properties and partial sequence. Proc. Natl. Acad. Sci. USA. 78:7594-7598. http://dx.doi.org/10.1073/pnas.78.12.7594
59. Nightingale, E.R. 1959. Phenomenological theory of ion solvation. Effective radii of hydrated ions. J. Phys. Chemistry. 63:1381-1387. http://dx.doi.org/10.1021/j150579a011
60. Noskov, S.Y., W. Im, and B. Roux. 2004. Ion permeation through the alpha-hemolysin channel: theoretical studies based on Brownian dynamics and Poisson-Nernst-Plank electrodiffusion theory. Biophys. J. 87:2299-2309. http://dx.doi.org/10.1529/biophysj.104.044008
61. Oh, S., Y. Ri, M.V. Bennett, E.B. Trexler, V.K. Verselis, and T.A. Bargiello. 1997. Changes in permeability caused by connexin 32 mutations underlie X-linked Charcot-Marie-Tooth disease. Neuron. 19:927-938. http://dx.doi.org/10.1016/S0896-6273(00)80973-3
62. Oh, S., J.B. Rubin, M.V. Bennett, V.K. Verselis, and T.A. Bargiello. 1999. Molecular determinants of electrical rectification of single channel conductance in gap junctions formed by connexins 26 and 32. J. Gen. Physiol. 114:339-364. http://dx.doi.org/10.1085/jgp.114.3.339
63. Oh, S., V.K. Verselis, and T.A. Bargiello. 2008. Charges dispersed over the permeation pathway determine the charge selectivity and conductance of a Cx32 chimeric hemichannel. J. Physiol. 586:2445-2461. http://dx.doi.org/10.1113/jphysiol.2008.150805
64. Olsson, M.H.M., C.R. Søndergaard, M. Rostkowski, and J.H. Jensen. 2011. PROPKA3: Consistent treatment of internal and surface residues in empirical pKa predictions. J. Chem. Theory Comput. 7: 525-537. http://dx.doi.org/10.1021/ct100578z
65. Oshima, A., K. Tani, Y. Hiroaki, Y. Fujiyoshi, and G.E. Sosinsky. 2007. Three-dimensional structure of a human connexin26 gap junction channel reveals a plug in the vestibule. Proc. Natl. Acad. Sci. USA. 104:10034-10039. http://dx.doi.org/10.1073/pnas.0703704104
66. Phillips, J.C., R. Braun, W. Wang, J. Gumbart, E. Tajkhorshid, E. Villa, C. Chipot, R.D. Skeel, L. Kalé, and K. Schulten. 2005. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26:1781-1802. http://dx.doi.org/10.1002/jcc.20289
67. Polevoda, B., T. Arnesen, and F. Sherman. 2009. A synopsis of eukaryotic Nalpha-terminal acetyltransferases: nomenclature, subunits and substrates. BMC Proc. 3:S2. http://dx.doi.org/10.1186/1753-6561-3-s6-s2
68. Purnick, P.E., D.C. Benjamin, V.K. Verselis, T.A. Bargiello, and T.L. Dowd. 2000. Structure of the amino terminus of a gap junction protein. Arch. Biochem. Biophys. 381:181-190. http://dx.doi.org/10.1006/abbi.2000.1989
69. Rathmell, J.C., and C.B. Newgard. 2009. Biochemistry. A glucoseto-gene link. Science. 324:1021-1022. http://dx.doi.org/10.1126/science.1174665
70. Roux, B., T. Allen, S. Bernèche, and W. Im. 2004. Theoretical and computational models of biological ion channels. Q. Rev. Biophys. 37:15-103. http://dx.doi.org/10.1017/S0033583504003968
71. Rui, H., K.I. Lee, R.W. Pastor, and W. Im. 2011. Molecular dynamics studies of ion permeation in VDAC. Biophys. J. 100:602-610. http://dx.doi.org/10.1016/j.bpj.2010.12.3711
72. Sadoul, K., J. Wang, B. Diagouraga, and S. Khochbin. 2011. The tale of protein lysine acetylation in the cytoplasm. J. Biomed. Biotechnol. 2011:970382. http://dx.doi.org/10.1155/2011/970382
73. 2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome. J. Gen. Physiol. 136:47-62. http://dx.doi.org/10.1085/jgp.201010433
74. Shearer, D., W. Ens, K. Standing, and G. Valdimarsson. 2008. Posttranslational modifications in lens fiber connexins identified by off-line-HPLC MALDI-quadrupole time-of-flight mass spectrometry. Invest. Ophthalmol. Vis. Sci. 49:1553-1562
75. Sherman, F., J.W. Stewart, and S. Tsunasawa. 1985. Methionine or not methionine at the beginning of a protein. Bioessays. 3:27-31. http://dx.doi.org/10.1002/bies.950030108
76. Smart, O.S., J.G. Neduvelil, X. Wang, B.A. Wallace, and M.S. Sansom. 1996. HOLE: a program for the analysis of the pore dimensions of ion channel structural models. J. Mol. Graph. 14:354-360. http://dx.doi.org/10.1016/S0263-7855(97)00009-X
77. Starheim, K.K., D. Gromyko, R. Velde, J.E. Varhaug, and T. Arnesen. 2009. Composition and biological significance of the human Nalpha-terminal acetyltransferases. BMC Proc. 3:S3. http://dx.doi.org/10.1186/1753-6561-3-s6-s3
78. Suchyna, T.M., J.M. Nitsche, M. Chilton, A.L. Harris, R.D. Veenstra, and B.J. Nicholson. 1999. Different ionic selectivities for connexins 26 and 32 produce rectifying gap junction channels. Biophys. J. 77:2968-2987. http://dx.doi.org/10.1016/S0006-3495 (99)77129-8
79. Tang, Q., T.L. Dowd, V.K. Verselis, and T.A. Bargiello. 2009. Conformational changes in a pore-forming region underlie voltage-dependent "loop gating" of an unapposed connexin hemichannel. J. Gen. Physiol. 133:555-570. http://dx.doi.org/10.1085/jgp.200910207
80. Trexler, E.B., F.F. Bukauskas, J. Kronengold, T.A. Bargiello, and V.K. Verselis. 2000. The first extracellular loop domain is a major determinant of charge selectivity in connexin46 channels. Biophys. J. 79:3036-3051. http://dx.doi.org/10.1016/S0006-3495(00)76539-8
81. Unger, V.M., N.M. Kumar, N.B. Gilula, and M. Yeager. 1999. Threedimensional structure of a recombinant gap junction membrane channel. Science. 283:1176-1180. http://dx.doi.org/10.1126/science.283.5405.1176
82. Verselis, V.K. 2009. The connexin channel pore: pore-lining segments and residues. In In Connexins: A Guide. A.L. Harris and D. Locke, editors. Humana Press, New York. 77-102 pp.
83. Verselis, V.K., M.P. Trelles, C. Rubinos, T.A. Bargiello, and M. Srinivas. 2009. Loop gating of connexin hemichannels involves movement of pore-lining residues in the first extracellular loop domain. J. Biol. Chem. 284:4484-4493. http://dx.doi.org/10.1074/jbc.M807430200
84. Wellen, K.E., G. Hatzivassiliou, U.M. Sachdeva, T.V. Bui, J.R. Cross, and C.B. Thompson. 2009. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 324:1076-1080. http://dx.doi.org/10.1126/science.1164097
85. Woolf, T.B., and B. Roux. 1994. Molecular dynamics simulation of the gramicidin channel in a phospholipid bilayer. Proc. Natl. Acad. Sci. USA. 91:11631-11635. http://dx.doi.org/10.1073/pnas.91.24.11631
86. Woolf, T.B., and B. Roux. 1996. Structure, energetics, and dynamics of lipid-protein interactions: a molecular dynamics study of the gramicidin A channel in a DMPC bilayer. Proteins. 24:92-114. http://dx.doi.org/10.1002/(SICI)1097-0134(199601)24:1<92::AID-PROT7>3.0.CO;2-Q
87. Yang, X.-J. 2004. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res. 32:959-976. http://dx.doi.org/10.1093/nar/gkh252
88. Yang, X.-J., and E. Seto. 2008. Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol. Cell. 31:449-461. http://dx.doi.org/10.1016/j.molcel.2008.07.002
89. Zhao, H.B. 2005. Connexin26 is responsible for anionic molecule permeability in the cochlea for intercellular signalling and metabolic communications. Eur. J. Neurosci. 21:1859-1868. http://dx.doi.org/10.1111/j.1460-9568.2005.04031.x
90. Zhao, H.B., and N. Yu. 2006. Distinct and gradient distributions of connexin26 and connexin30 in the cochlear sensory epithelium of guinea pigs. J. Comp. Neurol. 499:506-518. http://dx.doi.org/10.1002/cne.21113
91. Zhou, X.W., A. Pfahnl, R. Werner, A. Hudder, A. Llanes, A. Luebke, and G. Dahl. 1997. Identification of a pore lining segment in gap junction hemichannels. Biophys. J. 72:1946-1953. http://dx.doi.org/10.1016/S0006-3495(97)78840-4
92. Zimmer, D.B., C.R. Green, W.H. Evans, and N.B. Gilula. 1987. Topological analysis of the major protein in isolated intact rat liver gap junctions and gap junction-derived single membrane structures. J. Biol. Chem. 262:7751-7763.