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An Assessment of How VDAC Structures Have Impacted Our Understanding of Their Function

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Molecular Basis for Mitochondrial Signaling

Part of the book series: Biological and Medical Physics, Biomedical Engineering ((BIOMEDICAL))

Abstract

The voltage-dependent anion channel (VDAC) is responsible for ion and metabolite flow across the mitochondrial outer membrane and is a vital component of mitochondrial regulation. After decades of biochemical and biophysical work, three structures of VDAC1 were solved, generating a new platform for probing VDAC’s function. This milestone accomplishment led to major findings in the VDAC field while generating many new fundamental questions regarding channel regulation such as the architecture of the closed state, the mechanisms for gating the channel, and the mode of binding for proteins known to interact with VDAC. This chapter highlights some of the key discoveries in VDAC research since the release of these structures and further explores the remaining challenges that must be overcome to provide a complete understanding of VDAC’s function in the cell.

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Notes

  1. 1.

    For a comprehensive list of all residues, on all multipass membrane proteins predicted to be electrostatically destabilizing in the membrane, please see Ref. Marcoline et al. (2015).

References

  • Bayrhuber M, Meins T, Habeck M, Becker S, Giller K, Villinger S, Vonrhein C, Griesinger C, Zweckstetter M, Zeth K (2008) Structure of the human voltage-dependent anion channel. Proc Natl Acad Sci U S A 105:15370–15375

    Article  ADS  Google Scholar 

  • Chaptal V, Ujwal R, Nie Y, Watanabe A, Kwon S, Abramson J (2010) Fluorescence detection of heavy atom labeling (FD-HAL): a rapid method for identifying covalently modified cysteine residues by phasing atoms. J Struct Biol 171:82–87

    Article  Google Scholar 

  • Cheng EH, Sheiko TV, Fisher JK, Craigen WJ, Korsmeyer SJ (2003) VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science 301:513–517

    Article  ADS  Google Scholar 

  • Choudhary OP, Ujwal R, Kowallis W, Coalson R, Abramson J, Grabe M (2010) The electrostatics of VDAC: implications for selectivity and gating. J Mol Biol 396:580–592

    Article  Google Scholar 

  • Choudhary OP, Paz A, Adelman JL, Colletier JP, Abramson J, Grabe M (2014) Structure-guided simulations illuminate the mechanism of ATP transport through VDAC1. Nat Struct Mol Biol 21:626–632

    Article  Google Scholar 

  • Colombini M (1989) Voltage gating in the mitochondrial channel, VDAC. J Membr Biol 111:103–111

    Article  Google Scholar 

  • Colombini M (2009) The published 3D structure of the VDAC channel: native or not? Trends Biochem Sci 34:382–389

    Article  Google Scholar 

  • Craigen WJ, Graham BH (2008) Genetic strategies for dissecting mammalian and Drosophila voltage-dependent anion channel functions. J Bioenerg Biomembr 40:207–212

    Article  Google Scholar 

  • De Pinto V, Prezioso G, Thinnes F, Link TA, Palmieri F (1991) Peptide-specific antibodies and proteases as probes of the transmembrane topology of the bovine heart mitochondrial porin. Biochemistry 30:10191–10200

    Article  Google Scholar 

  • De Pinto V, Al Jamal JA, Palmieri F (1993) Location of the dicyclohexylcarbodiimide-reactive glutamate residue in the bovine heart mitochondrial porin. J Biol Chem 268:12977–12982

    Google Scholar 

  • Elston T, Wang H, Oster G (1998) Energy transduction in ATP synthase. Nature 391:510–513

    Article  ADS  Google Scholar 

  • Fan J, Papadopoulos V (2013) Evolutionary origin of the mitochondrial cholesterol transport machinery reveals a universal mechanism of steroid hormone biosynthesis in animals. PLoS One 8:e76701

    Article  ADS  Google Scholar 

  • Forte M, Guy HR, Mannella CA (1987) Molecular genetics of the VDAC ion channel: structural model and sequence analysis. J Bioenerg Biomembr 19:341–350

    Article  Google Scholar 

  • Ge L, Villinger S, Mari SA, Giller K, Griesinger C, Becker S, Muller DJ, Zweckstetter M (2016) Molecular plasticity of the human voltage-dependent Anion Channel embedded into a membrane. Structure 24:585–594

    Article  Google Scholar 

  • Goncalves RP, Buzhynskyy N, Prima V, Sturgis JN, Scheuring S (2007) Supramolecular assembly of VDAC in native mitochondrial outer membranes. J Mol Biol 369:413–418

    Article  Google Scholar 

  • Hiller S, Garces RG, Malia TJ, Orekhov VY, Colombini M, Wagner G (2008) Solution structure of the integral human membrane protein VDAC-1 in detergent micelles. Science 321:1206–1210

    Article  ADS  Google Scholar 

  • Hiller S, Abramson J, Mannella C, Wagner G, Zeth K (2010) The 3D structures of VDAC represent a native conformation. Trends Biochem Sci 35:514–521

    Article  Google Scholar 

  • Hoogenboom BW, Suda K, Engel A, Fotiadis D (2007) The supramolecular assemblies of voltage-dependent anion channels in the native membrane. J Mol Biol 370:246–255

    Article  Google Scholar 

  • Im W, Roux B (2002) Ion permeation and selectivity of OmpF porin: a theoretical study based on molecular dynamics, Brownian dynamics, and continuum electrodiffusion theory. J Mol Biol 322:851–869

    Article  Google Scholar 

  • Israelson A, Abu-Hamad S, Zaid H, Nahon E, Shoshan-Barmatz V (2007) Localization of the voltage-dependent anion channel-1 Ca2+-binding sites. Cell Calcium 41:235–244

    Article  Google Scholar 

  • Jaburek M, Garlid KD (2003) Reconstitution of recombinant uncoupling proteins: UCP1, -2, and -3 have similar affinities for ATP and are unaffected by coenzyme Q10. J Biol Chem 278:25825–25831

    Article  Google Scholar 

  • Keinan N, Tyomkin D, Shoshan-Barmatz V (2010) Oligomerization of the mitochondrial protein voltage-dependent anion channel is coupled to the induction of apoptosis. Mol Cell Biol 30:5698–5709

    Article  Google Scholar 

  • Keinan N, Pahima H, Ben-Hail D, Shoshan-Barmatz V (2013) The role of calcium in VDAC1 oligomerization and mitochondria-mediated apoptosis. Biochim Biophys Acta 1833:1745–1754

    Article  Google Scholar 

  • Koppel DA, Kinnally KW, Masters P, Forte M, Blachly-Dyson E, Mannella CA (1998) Bacterial expression and characterization of the mitochondrial outer membrane channel. Effects of n-terminal modifications. J Biol Chem 273:13794–13800

    Article  Google Scholar 

  • Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH (2000) Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 7:1166–1173

    Article  Google Scholar 

  • Krammer EM, Homble F, Prevost M (2011) Concentration dependent ion selectivity in VDAC: a molecular dynamics simulation study. PLoS One 6:e27994

    Article  ADS  Google Scholar 

  • Kuszak AJ, Jacobs D, Gurnev PA, Shiota T, Louis JM, Lithgow T, Bezrukov SM, Rostovtseva TK, Buchanan SK (2015) Evidence of distinct channel conformations and substrate binding affinities for the mitochondrial outer membrane protein translocase pore Tom40. J Biol Chem 290:26204–26217

    Article  Google Scholar 

  • Law RH, Lukoyanova N, Voskoboinik I, Caradoc-Davies TT, Baran K, Dunstone MA, D’Angelo ME, Orlova EV, Coulibaly F, Verschoor S, Browne KA, Ciccone A, Kuiper MJ, Bird PI, Trapani JA, Saibil HR, Whisstock JC (2010) The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature 468:447–451

    Article  ADS  Google Scholar 

  • Marcoline FV, Bethel N, Guerriero CJ, Brodsky JL, Grabe M (2015) Membrane protein properties revealed through data-rich electrostatics calculations. Structure 23:1526–1537

    Article  Google Scholar 

  • Mertins B, Psakis G, Grosse W, Back KC, Salisowski A, Reiss P, Koert U, Essen LO (2012) Flexibility of the N-terminal mVDAC1 segment controls the channel’s gating behavior. PLoS One 7:e47938

    Article  ADS  Google Scholar 

  • Mondal S, Khelashvili G, Shi L, Weinstein H (2013) The cost of living in the membrane: a case study of hydrophobic mismatch for the multi-segment protein LeuT. Chem Phys Lipids 169:27–38

    Article  Google Scholar 

  • Naghdi S, Varnai P, Hajnoczky G (2015) Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis. Proc Natl Acad Sci U S A 112:E5590–E5599

    Article  ADS  Google Scholar 

  • Noskov SY, Rostovtseva TK, Bezrukov SM (2013) ATP transport through VDAC and the VDAC-tubulin complex probed by equilibrium and nonequilibrium MD simulations. Biochemistry 52:9246–9256

    Article  Google Scholar 

  • Noskov SY, Rostovtseva TK, Chamberlin AC, Teijido O, Jiang W, Bezrukov SM (2016) Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC). Biochim Biophys Acta 1858:1778–1790

    Article  Google Scholar 

  • Popot JL, Gerchman SE, Engelman DM (1987) Refolding of bacteriorhodopsin in lipid bilayers. A thermodynamically controlled two-stage process. J Mol Biol 198:655–676

    Article  Google Scholar 

  • Rostovtseva TK, Bezrukov SM (1998) ATP transport through a single mitochondrial channel, VDAC, studied by current fluctuation analysis. Biophys J 74:2365–2373

    Article  Google Scholar 

  • Rostovtseva TK, Bezrukov SM (2008) VDAC regulation: role of cytosolic proteins and mitochondrial lipids. J Bioenerg Biomembr 40:163–170

    Article  Google Scholar 

  • Rostovtseva T, Colombini M (1996) ATP flux is controlled by a voltage-gated channel from the mitochondrial outer membrane. J Biol Chem 271:28006–28008

    Article  Google Scholar 

  • Rostovtseva T, Colombini M (1997) VDAC channels mediate and gate the flow of ATP: implications for the regulation of mitochondrial function. Biophys J 72:1954–1962

    Article  Google Scholar 

  • Rostovtseva TK, Komarov A, Bezrukov SM, Colombini M (2002) Dynamics of nucleotides in VDAC channels: structure-specific noise generation. Biophys J 82:193–205

    Article  Google Scholar 

  • Rostovtseva TK, Kazemi N, Weinrich M, Bezrukov SM (2006) Voltage gating of VDAC is regulated by nonlamellar lipids of mitochondrial membranes. J Biol Chem 281:37496–37506

    Article  Google Scholar 

  • Roy SS, Ehrlich AM, Craigen WJ, Hajnoczky G (2009) VDAC2 is required for truncated BID-induced mitochondrial apoptosis by recruiting BAK to the mitochondria. EMBO Rep 10:1341–1347

    Article  Google Scholar 

  • Rui H, Lee KI, Pastor RW, Im W (2011) Molecular dynamics studies of ion permeation in VDAC. Biophys J 100:602–610

    Article  Google Scholar 

  • Sampson MJ, Decker WK, Beaudet AL, Ruitenbeek W, Armstrong D, Hicks MJ, Craigen WJ (2001) Immotile sperm and infertility in mice lacking mitochondrial voltage-dependent anion channel type 3. J Biol Chem 276:39206–39212

    Article  Google Scholar 

  • Schein SJ, Colombini M, Finkelstein A (1976) Reconstitution in planar lipid bilayers of a voltage-dependent anion-selective channel obtained from paramecium mitochondria. J Membr Biol 30:99–120

    Article  Google Scholar 

  • Schoppa NE, Mccormack K, Tanouye MA, Sigworth FJ (1992) The size of gating charge in wild-type and mutant Shaker potassium channels. Science 255:1712–1715

    Article  ADS  Google Scholar 

  • Schredelseker J, Paz A, Lopez CJ, Altenbach C, Leung CS, Drexler MK, Chen JN, Hubbell WL, Abramson J (2014) High resolution structure and double electron-electron resonance of the zebrafish voltage-dependent anion channel 2 reveal an oligomeric population. J Biol Chem 289:12566–12577

    Article  Google Scholar 

  • Shanmugavadivu B, Apell HJ, Meins T, Zeth K, Kleinschmidt JH (2007) Correct folding of the beta-barrel of the human membrane protein VDAC requires a lipid bilayer. J Mol Biol 368:66–78

    Article  Google Scholar 

  • Shimizu H, Schredelseker J, Huang J, Lu K, Naghdi S, Lu F, Franklin S, Fiji HD, Wang K, Zhu H, Tian C, Lin B, Nakano H, Ehrlich A, Nakai J, Stieg AZ, Gimzewski JK, Nakano A, Goldhaber JI, Vondriska TM, Hajnoczky G, Kwon O, Chen JN (2015) Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity. Elife 4:e04801

    Google Scholar 

  • Shoshan-Barmatz V, Keinan N, Zaid H (2008) Uncovering the role of VDAC in the regulation of cell life and death. J Bioenerg Biomembr 40:183–191

    Article  Google Scholar 

  • Shoshan-Barmatz V, Ben-Hail D, Admoni L, Krelin Y, Tripathi SS (2015) The mitochondrial voltage-dependent anion channel 1 in tumor cells. Biochim Biophys Acta 1848:2547–2575

    Article  Google Scholar 

  • Stanley S, Dias JA, D’Arcangelis D, Mannella CA (1995) Peptide-specific antibodies as probes of the topography of the voltage-gated channel in the mitochondrial outer membrane of Neurospora crassa. J Biol Chem 270:16694–16700

    Article  Google Scholar 

  • Teijido O, Ujwal R, Hillerdal CO, Kullman L, Rostovtseva TK, Abramson J (2012) Affixing N-terminal alpha-helix to the wall of the voltage-dependent anion channel does not prevent its voltage gating. J Biol Chem 287:11437–11445

    Article  Google Scholar 

  • Teijido O, Rappaport SM, Chamberlin A, Noskov SY, Aguilella VM, Rostovtseva TK, Bezrukov SM (2014) Acidification asymmetrically affects voltage-dependent anion channel implicating the involvement of salt bridges. J Biol Chem 289:23670–23682

    Article  Google Scholar 

  • Tomasello MF, Guarino F, Reina s, Messina A, De Pinto V (2013) The voltage-dependent anion selective channel 1 (VDAC1) topography in the mitochondrial outer membrane as detected in intact cell. PLoS One 8:e81522

    Article  ADS  Google Scholar 

  • Tornroth-Horsefield S, Neutze R (2008) Opening and closing the metabolite gate. Proc Natl Acad Sci U S A 105:19565–19566

    Article  ADS  Google Scholar 

  • Ujwal R, Abramson, J (2012) High-throughput crystallization of membrane proteins using the lipidic bicelle method. J Vis Exp 59:e3383

    Google Scholar 

  • Ujwal R, Cascio D, Colletier JP, Faham S, Zhang J, Toro L, Ping P, Abramson J (2008) The crystal structure of mouse VDAC1 at 2.3 A resolution reveals mechanistic insights into metabolite gating. Proc Natl Acad Sci U S A 105:17742–17747

    Article  ADS  Google Scholar 

  • Ujwal R, Cascio D, Chaptal V, Ping P, Abramson J (2009) Crystal packing analysis of murine VDAC1 crystals in a lipidic environment reveals novel insights on oligomerization and orientation. Channels (Austin) 3:167–170

    Article  Google Scholar 

  • Valiyaveetil F, Hermolin J, Fillingame RH (2002) pH dependent inactivation of solubilized F1F0 ATP synthase by dicyclohexylcarbodiimide: pK(a) of detergent unmasked aspartyl-61 in Escherichia coli subunit c. Biochim Biophys Acta 1553:296–301

    Article  Google Scholar 

  • Villinger s, Briones R, Giller K, Zachariae U, Lange A, De Groot BL, Griesinger C, Becker S, Zweckstetter M (2010) Functional dynamics in the voltage-dependent anion channel. Proc Natl Acad Sci U S A 107:22546–22551

    Article  ADS  Google Scholar 

  • Vyssokikh MY, Brdiczka D (2003) The function of complexes between the outer mitochondrial membrane pore (VDAC) and the adenine nucleotide translocase in regulation of energy metabolism and apoptosis. Acta Biochim Pol 50:389–404

    Google Scholar 

  • Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, Macgregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730

    Article  ADS  Google Scholar 

  • Yamamoto T, Yamada A, Watanabe M, Yoshimura Y, Yamazaki N, Yoshimura Y, Yamauchi T, Kataoka M, Nagata T, Terada H, Shinohara Y (2006) VDAC1, having a shorter N-terminus than VDAC2 but showing the same migration in an SDS-polyacrylamide gel, is the predominant form expressed in mitochondria of various tissues. J Proteome Res 5:3336–3344

    Article  Google Scholar 

  • Yehezkel G, Hadad N, Zaid H, Sivan S, Shoshan-Barmatz V (2006) Nucleotide-binding sites in the voltage-dependent anion channel: characterization and localization. J Biol Chem 281:5938–5946

    Article  Google Scholar 

  • Zachariae U, Schneider R, Briones R, Gattin Z, Demers JP, Giller K, Maier E, Zweckstetter M, Griesinger C, Becker S, Benz R, De Groot BL, LANGE A (2012) Beta-barrel mobility underlies closure of the voltage-dependent anion channel. Structure 20:1540–1549

    Article  Google Scholar 

  • Zalk R, Israelson A, Garty ES, Azoulay-Zohar H, Shoshan-Barmatz V (2005) Oligomeric states of the voltage-dependent anion channel and cytochrome c release from mitochondria. Biochem J 386:73–83

    Article  Google Scholar 

  • Zeth K (2010) Structure and evolution of mitochondrial outer membrane proteins of beta-barrel topology. Biochim Biophys Acta 1797:1292–1299

    Article  Google Scholar 

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Acknowledgment

This work was supported by the National Institutes of Health Grant R01 GM 089740 (Grabe) and R01GM078844 (Abramson).

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Authors and Affiliations

  1. Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Lucie Bergdoll & Jeff Abramson

  2. Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA

    Michael Grabe

  3. Institute for Stem Cell Biology and Regenerative Medicine (inStem), National Centre for Biological Sciences–Tata Institute of Fundamental Research, Bellary Road, Bangalore, 560065, Karnataka, India

    Jeff Abramson

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  1. Lucie Bergdoll
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  2. Michael Grabe
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  3. Jeff Abramson
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Correspondence to Jeff Abramson .

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  1. Section on Molecular Transport, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

    Tatiana K. Rostovtseva

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Bergdoll, L., Grabe, M., Abramson, J. (2017). An Assessment of How VDAC Structures Have Impacted Our Understanding of Their Function. In: Rostovtseva, T. (eds) Molecular Basis for Mitochondrial Signaling. Biological and Medical Physics, Biomedical Engineering. Springer, Cham. https://doi.org/10.1007/978-3-319-55539-3_6

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