How far can we go with structural mass spectrometry of protein complexes?

Critical Insight

Abstract

Physical interactions between proteins and the formation of stable complexes form the basis of most biological functions. Therefore, a critical step toward understanding the integrated workings of the cell is to determine the structure of protein complexes, and reveal how their structural organization dictates function. Studying the three-dimensional organization of protein assemblies, however, represents a major challenge for structural biologists, due to the large size of the complexes, their heterogeneous composition, their flexibility, and their asymmetric structure. In the last decade, mass spectrometry has proven to be a valuable tool for analyzing such noncovalent complexes. Here, I illustrate the breadth of structural information that can be obtained from this approach, and the steps taken to elucidate the stoichiometry, topology, packing, dynamics, and shape of protein complexes. In addition, I illustrate the challenges that lie ahead, and the future directions toward which the field might be heading.

References

  1. 1.
    Lander, E. S.; Linton, L. M.; Birren, B.; Nusbaum, C.; Zody, M. C.; Baldwin, J.; Devon, K.; Dewar, K.; Doyle, M.; FitzHugh, W.; Funke, R.; Gage, D.; Harris, K.; Heaford, A.; Howland, J.; Kann, L.; Lehoczky, J.; LeVine, R.; McEwan, P.; McKernan, K.; Meldrim, J.; Mesirov, J. P.; Miranda, C.; Morris, W.; Naylor, J.; Raymond, C.; Rosetti, M.; Santos, R.; Sheridan, A.; Sougnez, C.; Stange-Thomann, N.; Stojanovic, N.; Subramanian, A.; Wyman, D.; Rogers, J.; Sulston, J.; Ainscough, R.; Beck, S.; Bentley, D.; Burton, J.; Clee, C.; Carter, N.; Coulson, A.; Deadman, R.; Deloukas, P.; Dunham, A.; Dunham, I.; Durbin, R.; French, L.; Grafham, D.; Gregory, S.; Hubbard, T.; Humphray, S.; Hunt, A.; Jones, M.; Lloyd, C.; McMurray, A.; Matthews, L.; Mercer, S.; Milne, S.; Mullikin, J. C.; Mungall, A.; Plumb, R.; Ross, M.; Shownkeen, R.; Sims, S.; Waterston, R. H.; Wilson, R. K.; Hillier, L. W.; McPherson, J. D.; Marra, M. A.; Mardis, E. R.; Fulton, L. A.; Chinwalla, A. T.; Pepin, K. H.; Gish, W. R.; Chissoe, S. L.; Wendl, M. C.; Delehaunty, K. D.; Miner, T. L.; Delehaunty, A.; Kramer, J. B.; Cook, L. L.; Fulton, R. S.; Johnson, D. L.; Minx, P. J.; Clifton, S. W.; Hawkins, T.; Branscomb, E.; Predki, P.; Richardson, P.; Wenning, S.; Slezak, T.; Doggett, N.; Cheng, J. F.; Olsen, A.; Lucas, S.; Elkin, C.; Uberbacher, E.; Frazier, M.; Gibbs, R. A.; Muzny, D. M.; Scherer, S. E.; Bouck, J. B.; Sodergren, E. J.; Worley, K. C.; Rives, C. M.; Gorrell, J. H.; Metzker, M. L.; Naylor, S. L.; Kucherlapati, R. S.; Nelson, D. L.; Weinstock, G. M.; Sakaki, Y.; Fujiyama, A.; Hattori, M.; Yada, T.; Toyoda, A.; Itoh, T.; Kawagoe, C.; Watanabe, H.; Totoki, Y.; Taylor, T.; Weissenbach, J.; Heilig, R.; Saurin, W.; Artiguenave, F.; Brottier, P.; Bruls, T.; Pelletier, E.; Robert, C.; Wincker, P.; Smith, D. R.; Doucette-Stamm, L.; Rubenfield, M.; Weinstock, K.; Lee, H. M.; Dubois, J.; Rosenthal, A.; Platzer, M.; Nyakatura, G.; Taudien, S.; Rump, A.; Yang, H.; Yu, J.; Wang, J.; Huang, G.; Gu, J.; Hood, L.; Rowen, L.; Madan, A.; Qin, S.; Davis, R. W.; Federspiel, N. A.; Abola, A. P.; Proctor, M. J.; Myers, R. M.; Schmutz, J.; Dickson, M.; Grimwood, J.; Cox, D. R.; Olson, M. V.; Kaul, R.; Shimizu, N.; Kawasaki, K.; Minoshima, S.; Evans, G. A.; Athanasiou, M.; Schultz, R.; Roe, B. A.; Chen, F.; Pan, H.; Ramser, J.; Lehrach, H.; Reinhardt, R.; McCombie, W. R.; de la Bastide, M.; Dedhia, N.; Blocker, H.; Hornischer, K.; Nordsiek, G.; Agarwala, R.; Aravind, L.; Bailey, J. A.; Bateman, A.; Batzoglou, S.; Birney, E.; Bork, P.; Brown, D. G.; Burge, C. B.; Cerutti, L.; Chen, H. C.; Church, D.; Clamp, M.; Copley, R. R.; Doerks, T.; Eddy, S. R.; Eichler, E. E.; Furey, T. S.; Galagan, J.; Gilbert, J. G.; Harmon, C.; Hayashizaki, Y.; Haussler, D.; Hermjakob, H.; Hokamp, K.; Jang, W.; Johnson, L. S.; Jones, T. A.; Kasif, S.; Kaspryzk, A.; Kennedy, S.; Kent, W. J.; Kitts, P.; Koonin, E. V.; Korf, I.; Kulp, D.; Lancet, D.; Lowe, T. M.; McLysaght, A.; Mikkelsen, T.; Moran, J. V.; Mulder, N.; Pollara, V. J.; Ponting, C. P.; Schuler, G.; Schultz, J.; Slater, G.; Smit, A. F.; Stupka, E.; Szustakowski, J.; Thierry-Mieg, D.; Thierry-Mieg, J.; Wagner, L.; Wallis, J.; Wheeler, R.; Williams, A.; Wolf, Y. I.; Wolfe, K. H.; Yang, S. P.; Yeh, R. F.; Collins, F.; Guyer, M. S.; Peterson, J.; Felsenfeld, A.; Wetterstrand, K. A.; Patrinos, A.; Morgan, M. J.; de Jong, P.; Catanese, J. J.; Osoegawa, K.; Shizuya, H.; Choi, S.; Chen, Y. J. Initial Sequencing and Analysis of the Human Genome. Nature. 2001, 409, 860–921.CrossRefGoogle Scholar
  2. 2.
    Venter, J. C.; Adams, M. D.; Myers, E. W.; Li, P. W.; Mural, R. J.; Sutton, G. G.; Smith, H. O.; Yandell, M.; Evans, C. A.; Holt, R. A.; Gocayne, J. D.; Amanatides, P.; Ballew, R. M.; Huson, D. H.; Wortman, J. R.; Zhang, Q.; Kodira, C. D.; Zheng, X. H.; Chen, L.; Skupski, M.; Subramanian, G.; Thomas, P. D.; Zhang, J.; Gabor Miklos, G. L.; Nelson, C.; Broder, S.; Clark, A. G.; Nadeau, J.; McKusick, V. A.; Zinder, N.; Levine, A. J.; Roberts, R. J.; Simon, M.; Slayman, C.; Hunkapiller, M.; Bolanos, R.; Delcher, A.; Dew, I.; Fasulo, D.; Flanigan, M.; Florea, L.; Halpern, A.; Hannenhalli, S.; Kravitz, S.; Levy, S.; Mobarry, C.; Reinert, K.; Remington, K.; Abu-Threideh, J.; Beasley, E.; Biddick, K.; Bonazzi, V.; Brandon, R.; Cargill, M.; Chandramouliswaran, I.; Charlab, R.; Chaturvedi, K.; Deng, Z.; Di Francesco, V.; Dunn, P.; Eilbeck, K.; Evangelista, C.; Gabrielian, A. E.; Gan, W.; Ge, W.; Gong, F.; Gu, Z.; Guan, P.; Heiman, T. J.; Higgins, M. E.; Ji, R. R.; Ke, Z.; Ketchum, K. A.; Lai, Z.; Lei, Y.; Li, Z.; Li, J.; Liang, Y.; Lin, X.; Lu, F.; Merkulov, G. V.; Milshina, N.; Moore, H. M.; Naik, A. K.; Narayan, V. A.; Neelam, B.; Nusskern, D.; Rusch, D. B.; Salzberg, S.; Shao, W.; Shue, B.; Sun, J.; Wang, Z.; Wang, A.; Wang, X.; Wang, J.; Wei, M.; Wides, R.; Xiao, C.; Yan, C.; Yao, A.; Ye, J.; Zhan, M.; Zhang, W.; Zhang, H.; Zhao, Q.; Zheng, L.; Zhong, F.; Zhong, W.; Zhu, S.; Zhao, S.; Gilbert, D.; Baumhueter, S.; Spier, G.; Carter, C.; Cravchik, A.; Woodage, T.; Ali, F.; An, H.; Awe, A.; Baldwin, D.; Baden, H.; Barnstead, M.; Barrow, I.; Beeson, K.; Busam, D.; Carver, A.; Center, A.; Cheng, M. L.; Curry, L.; Danaher, S.; Davenport, L.; Desilets, R.; Dietz, S.; Dodson, K.; Doup, L.; Ferriera, S.; Garg, N.; Gluecksmann, A.; Hart, B.; Haynes, J.; Haynes, C.; Heiner, C.; Hladun, S.; Hostin, D.; Houck, J.; Howland, T.; Ibegwam, C.; Johnson, J.; Kalush, F.; Kline, L.; Koduru, S.; Love, A.; Mann, F.; May, D.; McCawley, S.; McIntosh, T.; McMullen, I.; Moy, M.; Moy, L.; Murphy, B.; Nelson, K.; Pfannkoch, C.; Pratts, E.; Puri, V.; Qureshi, H.; Reardon, M.; Rodriguez, R.; Rogers, Y. H.; Romblad, D.; Ruhfel, B.; Scott, R.; Sitter, C.; Smallwood, M.; Stewart, E.; Strong, R.; Suh, E.; Thomas, R.; Tint, N. N.; Tse, S.; Vech, C.; Wang, G.; Wetter, J.; Williams, S.; Williams, M.; Windsor, S.; Winn-Deen, E.; Wolfe, K.; Zaveri, J.; Zaveri, K.; Abril, J. F.; Guigo, R.; Campbell, M. J.; Sjolander, K. V.; Karlak, B.; Kejariwal, A.; Mi, H.; Lazareva, B.; Hatton, T.; Narechania, A.; Diemer, K.; Muruganujan, A.; Guo, N.; Sato, S.; Bafna, V.; Istrail, S.; Lippert, R.; Schwartz, R.; Walenz, B.; Yooseph, S.; Allen, D.; Basu, A.; Baxendale, J.; Blick, L.; Caminha, M.; Carnes-Stine, J.; Caulk, P.; Chiang, Y. H.; Coyne, M.; Dahlke, C.; Mays, A.; Dombroski, M.; Donnelly, M.; Ely, D.; Esparham, S.; Fosler, C.; Gire, H.; Glanowski, S.; Glasser, K.; Glodek, A.; Gorokhov, M.; Graham, K.; Gropman, B.; Harris, M.; Heil, J.; Henderson, S.; Hoover, J.; Jennings, D.; Jordan, C.; Jordan, J.; Kasha, J.; Kagan, L.; Kraft, C.; Levitsky, A.; Lewis, M.; Liu, X.; Lopez, J.; Ma, D.; Majoros, W.; McDaniel, J.; Murphy, S.; Newman, M.; Nguyen, T.; Nguyen, N.; Nodell, M.; Pan, S.; Peck, J.; Peterson, M.; Rowe, W.; Sanders, R.; Scott, J.; Simpson, M.; Smith, T.; Sprague, A.; Stockwell, T.; Turner, R.; Venter, E.; Wang, M.; Wen, M.; Wu, D.; Wu, M.; Xia, A.; Zandieh, A.; Zhu, X. The Sequence of the Human Genome. Science. 2001, 291, 1304–1351.CrossRefGoogle Scholar
  3. 3.
    Hart, G. T.; Ramani, A. K.; Marcotte, E. M. How Complete are Current Yeast and Human Protein-Interaction Networks? Genome Biol. 2006, 7, 120.CrossRefGoogle Scholar
  4. 4.
    Reguly, T.; Breitkreutz, A.; Boucher, L.; Breitkreutz, B. J.; Hon, G. C.; Myers, C. L.; Parsons, A.; Friesen, H.; Oughtred, R.; Tong, A.; Stark, C.; Ho, Y.; Botstein, D.; Andrews, B.; Boone, C.; Troyanskya, O. G.; Ideker, T.; Dolinski, K.; Batada, N. N.; Tyers, M. Comprehensive Curation and Analysis of Global Interaction Networks in Saccharomyces cerevisiae. J. Biol. 2006, 5, 11.CrossRefGoogle Scholar
  5. 5.
    Stumpf, M. P.; Thorne, T.; de Silva, E.; Stewart, R.; An, H. J.; Lappe, M.; Wiuf, C. Estimating the Size of the Human Interactome. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 6959–6964.CrossRefGoogle Scholar
  6. 6.
    Sharon, M.; Mao, H.; Boeri Erba, E.; Stephens, E.; Zheng, N.; Robinson, C. V. Symmetrical Modularity of the COP9 Signalosome Complex Suggests Its Multifunctionality. Structure. 2009, 17, 31–40.CrossRefGoogle Scholar
  7. 7.
    Robinson, C. V.; Sali, A.; Baumeister, W. The Molecular Sociology of the Cell. Nature. 2007, 450, 973–982.CrossRefGoogle Scholar
  8. 8.
    Sali, A.; Glaeser, R.; Earnest, T.; Baumeister, W. From Words to Literature in Structural Proteomics. Nature. 2003, 422, 216–225.CrossRefGoogle Scholar
  9. 9.
    Benesch, J. L.; Ruotolo, B. T.; Simmons, D. A.; Robinson, C. V. Protein Complexes in the Gas Phase: Technology for Structural Genomics and Proteomics. Chem. Rev. 2007, 107, 3544–3567.CrossRefGoogle Scholar
  10. 10.
    Heck, A. J. Native Mass Spectrometry: A Bridge Between Interactomics and Structural biology. Nat. Methods. 2008, 5, 927–933.CrossRefGoogle Scholar
  11. 11.
    Loo, J. A. Studying Noncovalent Protein Complexes by Electrospray Ionization Mass Spectrometry. Mass Spectrom. Rev. 1997, 16, 1–23.CrossRefGoogle Scholar
  12. 12.
    Sharon, M.; Robinson, C. V. The Role of Mass Spectrometry in Structure Elucidation of Dynamic Protein Complexes. Annu. Rev. Biochem. 2007, 76, 167–193.CrossRefGoogle Scholar
  13. 13.
    van den Heuvel, R. H.; Heck, A. J. Native Protein Mass Spectrometry: From Intact Oligomers to Functional Machineries. Curr. Opin. Chem. Biol. 2004, 8, 519–526.CrossRefGoogle Scholar
  14. 14.
    Ganem, B.; Li, Y. T.; Henion, J. D. Detection of Noncovalent Receptor-Ligand Complexes by Mass Spectrometry. J Am. Chem. Soc. 1991, 113, 6294–6296.CrossRefGoogle Scholar
  15. 15.
    Ganem, B.; Li, Y. T.; Henion, J. D. Observation of Noncovalent Enzyme-Substrate and Enzyme-Product Complexes by Ion-Spray Mass Spectrometry. J. Am. Chem. Soc. 1991, 113, 7818–7819.CrossRefGoogle Scholar
  16. 16.
    Karasa, M.; Bahra, U.; Ingendoha, A.; Nordhoffa, E.; Stahla, B.; Strupata, K.; Hillenkamp, F. Principles and Applications of Matrix-Assisted UV-Laser Desorption/Ionization Mass Spectrometry. Anal. Chim. Acta. 1990, 241, 175–185.CrossRefGoogle Scholar
  17. 17.
    Videler, H.; Ilag, L. L.; McKay, A. R.; Hanson, C. L.; Robinson, C. V. Mass Spectrometry of Intact Ribosomes. FEBS Lett. 2005, 579, 943–947.CrossRefGoogle Scholar
  18. 18.
    Uetrecht, C.; Versluis, C.; Watts, N. R.; Roos, W. H.; Wuite, G. J.; Wingfield, P. T.; Steven, A. C.; Heck, A. J. High-Resolution Mass Spectrometry of Viral Assemblies: Molecular Composition and Stability of Dimorphic Hepatitis B Virus Capsids. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 9216–9220.CrossRefGoogle Scholar
  19. 19.
    Uetrecht, C.; Versluis, C.; Watts, N. R.; Wingfield, P. T.; Steven, A. C.; Heck, A. J. Stability and Shape of Hepatitis B Virus Capsids In Vacuo. Angew. Chem. Int. Ed. Engl. 2008, 47, 6247–6251.CrossRefGoogle Scholar
  20. 20.
    Morton, V. L.; Stockley, P. G.; Stonehouse, N. J.; Ashcroft, A. E. Insights into Virus Capsid Assembly from Noncovalent Mass Spectrometry. Mass Spectrom. Rev. 2008, 27, 575–595.CrossRefGoogle Scholar
  21. 21.
    van Duijn, E.; Simmons, D. A.; van den Heuvel, R. H.; Bakkes, P. J.; van Heerikhuizen, H.; Heeren, R. M.; Robinson, C. V.; van der Vies, S. M.; Heck, A. J. Tandem Mass Spectrometry of Intact GroEL-Substrate Complexes Reveals Substrate-Specific Conformational Changes in the trans Ring. J Am. Chem. Soc. 2006, 128, 4694–4702.CrossRefGoogle Scholar
  22. 22.
    van Duijn, E.; Heck, A. J.; van der Vies, S. M. Inter-Ring Communication Allows the GroEL Chaperonin Complex to Distinguish Between Different Substrates. Protein Sci. 2007, 16, 956–965.CrossRefGoogle Scholar
  23. 23.
    Sharon, M.; Witt, S.; Felderer, K.; Rockel, B.; Baumeister, W.; Robinson, C. V. 20S Proteasomes Have the Potential to Keep Substrates in Store for Continual Degradation. J. Biol. Chem. 2006, 281, 9569–9575.CrossRefGoogle Scholar
  24. 24.
    Aquilina, J. A.; Benesch, J. L.; Bateman, O. A.; Slingsby, C.; Robinson, C. V. Polydispersity of a Mammalian Chaperone: Mass Spectrometry Reveals the Population of Oligomers in αB-crystallin. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 10611–10616.CrossRefGoogle Scholar
  25. 25.
    Bich, C.; Zenobi, R. Mass Spectrometry of Large Complexes. Curr. Opin. Struct. Biol. 2009, 19, 632–639.CrossRefGoogle Scholar
  26. 26.
    Charvat, A.; Abel, B. How to Make Big Molecules Fly Out of Liquid Water: Applications, Features, and Physics of Laser Assisted Liquid Phase Dispersion Mass Spectrometry. Phys. Chem., Chem. Phys. 2007, 9, 3335–3360.CrossRefGoogle Scholar
  27. 27.
    Bolbach, G. Matrix-Assisted Laser Desorption/Ionization Analysis of Noncovalent Complexes: Fundamentals and Applications. Curr. Pharm. Des. 2005, 11, 2535–2557.CrossRefGoogle Scholar
  28. 28.
    Smith, D. L.; Zhang, Z. Probing Noncovalent Structural Interactions in Soybean Agglutinin by Electrofeatures of Proteins by Mass Spectrometry. Mass Spectrom. Rev. 1994, 13, 411–429.CrossRefGoogle Scholar
  29. 29.
    Smith, V. F.; Schwartz, B. L.; Randall, L. L.; Smith, R. D. Electrospray Mass Spectrometric Investigation of the Chaperone SecB. Protein Sci. 1996, 5, 488–494.CrossRefGoogle Scholar
  30. 30.
    Mcluckey, S. A. Principles of Collisional Activation in Analytical Mass Spectrometry. J Am. Soc. Mass Spectrom. 1992, 3, 599–614.CrossRefGoogle Scholar
  31. 31.
    Benesch, J. L.; Aquilina, J. A.; Ruotolo, B. T.; Sobott, F.; Robinson, C. V. Tandem Mass Spectrometry Reveals the Quaternary Organization of Macromolecular Assemblies. Chem. Biol. 2006, 13, 597–605.CrossRefGoogle Scholar
  32. 32.
    Chernushevich, I. V.; Thomson, B. A. Collisional Cooling of Large Ions in Electrospray Mass Spectrometry. Anal. Chem. 2004, 76, 1754–1760.CrossRefGoogle Scholar
  33. 33.
    Sobott, F.; Hernandez, H.; McCammon, M. G.; Tito, M. A.; Robinson, C. V. A Tandem Mass Spectrometer for Improved Transmission and Analysis of Large Macromolecular Assemblies. Anal. Chem. 2002, 74, 1402–1407.CrossRefGoogle Scholar
  34. 34.
    Hernandez, H.; Dziembowski, A.; Taverner, T.; Seraphin, B.; Robinson, C. V. Subunit Architecture of Multimeric Complexes Isolated Directly from cells. EMBO Rep. 2006, 7, 605–610.Google Scholar
  35. 35.
    Sharon, M.; Taverner, T.; Ambroggio, X. I.; Deshaies, R. J.; Robinson, C. V.; Structural Organization of the 19S Oroteasome Lid: Insights from MS of Intact Complexes. PLoS Biol. 2006, 4, e267.Google Scholar
  36. 36.
    Giles, K.; Pringle, S. D.; Worthington, K. R.; Little, D.; Wildgoose, J. L.; Bateman, R. H. Applications of a Traveling Wave-Based Radio-Frequency Only Stacked Ring Ion Guide. Rapid Commun. Mass Spectrom. 2004, 18, 2401–2414.CrossRefGoogle Scholar
  37. 37.
    Thalassinos, K.; Slade, S. E.; Jennings, K. R.; Scrivens, J. H.; Giles, K.; Wildgoose, J.; Hoyes, J.; Bateman, R. H.; Bowers, M. T. Ion Mobility Mass Spectrometry of Proteins in a Modified Commercial Mass Spectrometer. Int. J. Mass Spectrom. 2004, 236, 55–63.CrossRefGoogle Scholar
  38. 38.
    Zhou, M.; Sandercock, A. M.; Fraser, C. S.; Ridlova, G.; Stephens, E.; Schenauer, M. R.; Yokoi-Fong, T.; Barsky, D.; Leary, J. A.; Hershey, J. W.; Doudna, J. A.; Robinson, C. V. Mass Spectrometry Reveals Modularity and a Complete Subunit Interaction Map of the Eukaryotic Translation Factor eIF3. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 18139–18144.CrossRefGoogle Scholar
  39. 39.
    Ferrige, A. G.; Seddon, M. J.; Green, B. N.; Jarvis, S. A.; Skilling, J.; Staunton, J. Disentangling Electrospray Spectra with Maximum Entropy. Rapid Commun. Mass Spectrom. 1992, 6, 707–711.CrossRefGoogle Scholar
  40. 40.
    Ferrige, A. G.; Seddon, M. J.; Skilling, J.; Ordsmith, N. The Application of MaxEnt to High Resolution Mass Spectrometry. Mass Spectrom. 1992, 6, 765–770.Google Scholar
  41. 41.
    Taverner, T.; Hernandez, H.; Sharon, M.; Ruotolo, B. T.; Matak-Vinkovic, D.; Devos, D.; Russell, R. B.; Robinson, C. V. Subunit Architecture of Intact Protein Complexes from Mass Spectrometry and Homology Modeling. Acc. Chem. Res. 2008, 41, 617–627.CrossRefGoogle Scholar
  42. 42.
    van Breukelen, B.; Barendregt, A.; Heck, A. J.; van den Heuvel, R. H. Resolving Stoichiometries and Oligomeric States of Glutamate Synthase Protein Complexes with Curve Fitting and Simulation of Electrospray Mass Spectra. Rapid Commun. Mass Spectrom. 2006, 20, 2490–2496.CrossRefGoogle Scholar
  43. 43.
    McKay, A. R.; Ruotolo, B. T.; Ilag, L. L.; Robinson, C. V. Mass Measurements of Increased Accuracy Resolve Heterogeneous Populations of Intact Ribosomes. J. Am. Chem. Soc. 2006, 128, 11433–11442.CrossRefGoogle Scholar
  44. 44.
    Waugh, D. S. Making the Most of Affinity Tags. Trends Biotechnol. 2005, 23, 316–320.CrossRefGoogle Scholar
  45. 45.
    Brizzard, B. Epitope Yagging. Biotechniques. 2008, 44, 693–695.CrossRefGoogle Scholar
  46. 46.
    Benesch, J. L. P.; Aquilina, J. A.; Ruotolo, B. T.; Sobott, F.; Robinson, C. V. Tandem Mass Spectrometry Reveals the Quaternary Organization of Macromolecular Assemblies. Chem. Biol. 2006, 13, 597–605.CrossRefGoogle Scholar
  47. 47.
    Fandrich, M.; Tito, M. A.; Leroux, M. R.; Rostom, A. A.; Hartl, F. U.; Dobson, C. M.; Robinson, C. V. Observation of the Noncovalent Assembly and Disassembly Pathways of the Chaperone Complex MtGimC by Mass Spectrometry. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 14151–14155.CrossRefGoogle Scholar
  48. 48.
    Ilag, L. L.; Videler, H.; McKay, A. R.; Sobott, F.; Fucini, P.; Nierhaus, K. H.; Robinson, C. V. Heptameric (L12)6/L10 Rather Than Canonical Pentameric Complexes are Found by Tandem MS of Intact Ribosomes from Thermophilic Bacteria. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 8192–8197.CrossRefGoogle Scholar
  49. 49.
    Zhang, Z.; Zheng, Y.; Mazon, H.; Milgrom, E.; Kitagawa, N.; Kish-Trier, E.; Heck, A. J.; Kane, P. M.; Wilkens, S. Structure of the Yeast Vacuolar ATPase. J. Biol. Chem. 2008, 283, 35983–35995.CrossRefGoogle Scholar
  50. 50.
    Loo, J. A.; Berhane, B.; Kaddis, C. S.; Wooding, K. M.; Xie, Y.; Kaufman, S. L.; Chernushevich, I. V. Electrospray Ionization Mass Spectrometry and Ion Mobility Analysis of the 20S Proteasome Complex. J. Am. Soc. Mass Spectrom. 2005, 16, 998–1008.CrossRefGoogle Scholar
  51. 51.
    Benesch, J. L.; Ruotolo, B. T.; Sobott, F.; Wildgoose, J.; Gilbert, A.; Bateman, R.; Robinson, C. V. Quadrupole-Time-of-Flight Mass Spectrometer Modified for Higher-Energy Dissociation Reduces Protein Assemblies to Peptide Fragments. Anal. Chem. 2009, 81, 1270–1274.CrossRefGoogle Scholar
  52. 52.
    Lomeli, S. H.; Yin, S.; Ogorzalek Loo, R. R.; Loo, J. A. Increasing Charge While Preserving Noncovalent Protein Complexes for ESI-MS. J Am. Soc. Mass Spectrom. 2009, 20, 593–596.CrossRefGoogle Scholar
  53. 53.
    Kaltashov, I. A.; Abzalimov, R. R. Do Ionic Charges in ESI-MS Provide Useful Information on Macromolecular Structure? J. Am. Soc. Mass Spectrom. 2008, 19, 1239–1246.CrossRefGoogle Scholar
  54. 54.
    Beardsley, R. L.; Jones, C. M.; Galhena, A. S.; Wysocki, V. H. Noncovalent Protein Tetramers and Pentamers with “n” Charges Yield Monomers with n/4 and n/5 Charges. Anal. Chem. 2009, 81, 1347–1356.CrossRefGoogle Scholar
  55. 55.
    Galhena, A. S.; Dagan, S.; Jones, C. M.; Beardsley, R. L.; Wysocki, V. H. Surface-Induced Dissociation of Peptides and Protein Complexes in a Quadrupole/Time-of-Flight Mass Spectrometer. Anal. Chem. 2008, 80, 1425–1436.CrossRefGoogle Scholar
  56. 56.
    Wysocki, V. H.; Jones, C. M.; Galhena, A. S.; Blackwell, A. E. Surface-Induced Dissociation Shows Potential to be More Informative Than Collision-Induced Dissociation for Structural Studies of Large Systems. J. Am. Soc. Mass Spectrom. 2008, 19, 903–913.CrossRefGoogle Scholar
  57. 57.
    Wysocki, V. H.; Joyce, K. E.; Jones, C. M.; Beardsley, R. L. Surface-Induced Dissociation of Small Molecules, Peptides, and Noncovalent Protein Complexes. J. Am. Soc. Mass Spectrom. 2008, 19, 190–208.CrossRefGoogle Scholar
  58. 58.
    Hernandez, H.; Robinson, C. V. Determining the Stoichiometry and Interactions of Macromolecular Assemblies from Mass Spectrometry. Nat. Protoc. 2007, 2, 715–726.CrossRefGoogle Scholar
  59. 59.
    Mason, E. R.; McDaniel, E. W. Transport Properties of Ions in Gases; John Wiley and Sons: New York 1988.CrossRefGoogle Scholar
  60. 60.
    Ruotolo, B. T.; Benesch, J. L.; Sandercock, A. M.; Hyung, S. J.; Robinson, C. V. Ion Mobility-Mass Spectrometry Analysis of Large Protein Complexes. Nat. Protoc. 2008, 3, 1139–1152.CrossRefGoogle Scholar
  61. 61.
    Ruotolo, B. T.; Giles, K.; Campuzano, I.; Sandercock, A. M.; Bateman, R. H.; Robinson, C. V. Evidence for Macromolecular Protein Rings in the Absence of Bulk Water. Science. 2005, 310, 1658–1661.CrossRefGoogle Scholar
  62. 62.
    van Duijn, E.; Barendregt, A.; Synowsky, S.; Versluis, C.; Heck, A. J. Chaperonin Complexes Monitored by Ion Mobility Mass Spectrometry. J. Am. Chem. Soc. 2009, 131, 1452–1459.CrossRefGoogle Scholar
  63. 63.
    Remaut, H.; Rose, R. J.; Hannan, T. J.; Hultgren, S. J.; Radford, S. E.; Ashcroft, A. E.; Waksman, G. Donor-Strand Exchange in Chaperone-Assisted Pilus Assembly Proceeds Through a Concerted β Strand Displacement Mechanism. Mol. Cell. 2006, 22, 831–842.CrossRefGoogle Scholar
  64. 64.
    Sharon, M.; Witt, S.; Glasmacher, E.; Baumeister, W.; Robinson, C. V. Mass Spectrometry Reveals the Missing Links in the Assembly Pathway of the Bacterial 20 S Proteasome. J. Biol. Chem. 2007, 282, 18448–18457.CrossRefGoogle Scholar
  65. 65.
    Levy, E. D.; Boeri Erba, E.; Robinson, C. V.; Teichmann, S. A. Assembly Reflects Evolution of Protein Complexes. Nature. 2008, 453, 1262–1265.CrossRefGoogle Scholar
  66. 66.
    Painter, A. J.; Jaya, N.; Basha, E.; Vierling, E.; Robinson, C. V.; Benesch, J. L. Real-Time Monitoring of Protein Complexes Reveals Their Quaternary Organization and Dynamics. Chem. Biol. 2008, 15, 246–253.CrossRefGoogle Scholar
  67. 67.
    Sun, Y.; MacRae, T. H. The Small Heat Shock Proteins and Their Role in Human Disease. FEBS J. 2005, 272, 2613–2627.CrossRefGoogle Scholar
  68. 68.
    Bova, M. P.; Ding, L. L.; Horwitz, J.; Fung, B. K. Subunit Exchange of αA-Crystallin. J. Biol. Chem. 1997, 272, 29511–29517.CrossRefGoogle Scholar
  69. 69.
    van den Oetelaar, P. J.; van Someren, P. F.; Thomson, J. A.; Siezen, R. J.; Hoenders, H. J. A Dynamic Quaternary Structure of Bovine α-Crystallin as Indicated from Intermolecular Exchange of Subunits. Biochemistry. 1990, 29, 3488–3493.CrossRefGoogle Scholar
  70. 70.
    Schneider, F.; Hammarstrom, P.; Kelly, J. W. Transthyretin Slowly Exchanges Subunits Under Physiologic Conditions: A Convenient Chromatographic Method to Study Subunit Exchange in Oligomeric Proteins. Protein Sci. 2001, 10, 1606–1613.CrossRefGoogle Scholar
  71. 71.
    Keetch, C. A.; Bromley, E. H.; McCammon, M. G.; Wang, N.; Christodoulou, J.; Robinson, C. V. L. 55P Transthyretin Accelerates Subunit Exchange and Leads to Rapid Formation of Hybrid Tetramers. J. Biol. Chem. 2005, 280, 41667–41674.CrossRefGoogle Scholar
  72. 72.
    Back, J. W.; de Jong, L.; Muijsers, A. O.; de Koster, C. G. Chemical Cross-Linking and Mass Spectrometry for Protein Structural Modeling. J. Mol. Biol. 2003, 331, 303–313.CrossRefGoogle Scholar
  73. 73.
    Sinz, A. Chemical Cross-Linking and Mass Spectrometry to Map Three-Dimensional Protein Structures and Protein-Protein Interactions. Mass Spectrom. Rev. 2006, 25, 663–682.CrossRefGoogle Scholar
  74. 74.
    Kolstoe, S. E.; Ridha, B. H.; Bellotti, V.; Wang, N.; Robinson, C. V.; Crutch, S. J.; Keir, G.; Kukkastenvehmas, R.; Gallimore, J. R.; Hutchinson, W. L.; Hawkins, P. N.; Wood, S. P.; Rossor, M. N.; Pepys, M. B. Molecular Dissection of Alzheimer’s Disease Neuropathology by Depletion of Serum Amyloid P Component. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 7619–7623.CrossRefGoogle Scholar
  75. 75.
    Jensen, O. N.; Barofsky, D. F.; Young, M. C.; von Hippel, P. H.; Swenson, S.; Seifried, S. E. Direct Observation of UV-Crosslinked Protein-Nucleic Acid Complexes by Matrix-Assisted Laser Desorption Ionization Mass Spectrometry. Rapid Commun. Mass Spectrom. 1993, 7, 496–501.CrossRefGoogle Scholar
  76. 76.
    Nazabal, A.; Wenzel, R. J.; Zenobi, R. Immunoassays with Direct Mass Spectrometric Detection. Anal. Chem. 2006, 78, 3562–3570.CrossRefGoogle Scholar
  77. 77.
    Farmer, T. B.; Caprioli, R. M. Determination of Protein-Protein Interactions by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry. J. Mass Spectrom. 1998, 33, 697–704.CrossRefGoogle Scholar
  78. 78.
    Back, J. W.; Hartog, A. F.; Dekker, H. L.; Muijsers, A. O.; de Koning, L. J.; de Jong, L. A New Crosslinker for Mass Spectrometric Analysis of the Quaternary Structure of Protein Complexes. J. Am. Soc. Mass Spectrom. 2001, 12, 222–227.CrossRefGoogle Scholar
  79. 79.
    Sinz, A. Chemical Cross-Linking and Mass Spectrometry for Mapping Three-Dimensional Structures of Proteins and Protein Complexes. J. Mass Spectrom. 2003, 38, 1225–1237.CrossRefGoogle Scholar
  80. 80.
    Young, M. M.; Tang, N.; Hempel, J. C.; Oshiro, C. M.; Taylor, E. W.; Kuntz, I. D.; Gibson, B. W.; Dollinger, G. High Throughput Protein Fold Identification by Using Experimental Constraints Derived from Intramolecular Cross-Links and Mass Spectrometry. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 5802–5806.CrossRefGoogle Scholar
  81. 81.
    Krauth, F.; Ihling, C. H.; Ruttinger, H. H.; Sinz, A. Heterobifunctional Isotope-Labeled Amine-Reactive Photo-Cross-Linker for Structural Investigation of Proteins by Matrix-Assisted Laser Desorption/Ionization Tandem Time-of-Flight and Electrospray Ionization LTQ-Orbitrap Mass Spectrometry. Rapid Commun. Mass Spectrom. 2009, 23, 2811–2818.CrossRefGoogle Scholar
  82. 82.
    Baca, M.; Kent, S. B. H. Direct Observation of a Ternary Complex Between the Dimeric Enzyme HIV-1 Protease and a Substrate-Based Inhibitor. J. Am. Chem. Soc. 1992, 114, 3992.CrossRefGoogle Scholar
  83. 83.
    Barrera, N. P.; Di Bartolo, N.; Booth, P. J.; Robinson, C. V. Micelles Protect Membrane Complexes from Solution to Vacuum. Science. 2008, 321, 243–246.CrossRefGoogle Scholar
  84. 84.
    Barrera, N. P.; Isaacson, S. C.; Zhou, M.; Bavro, V. N.; Welch, A.; Schaedler, T. A.; Seeger, M. A.; Miguel, R. N.; Korkhov, V. M.; van Veen, H. W.; Venter, H.; Walmsley, A. R.; Tate, C. G.; Robinson, C. V. Mass Spectrometry of Membrane Transporters Reveals Subunit Stoichiometry and Interactions. Nat. Methods. 2009, 6, 585–587.CrossRefGoogle Scholar
  85. 85.
    Lin, H. T.; Bavro, V. N.; Barrera, N. P.; Frankish, H. M.; Velamakanni, S.; van Veen, H. W.; Robinson, C. V.; Borges-Walmsley, M. I.; Walmsley, A. R. MacB ABC Transporter is a Dimer Whose ATPase Activity and Macrolide-Binding Capacity are Regulated by the Membrane Fusion Protein MacA. J Biol. Chem. 2009, 284, 1145–1154.CrossRefGoogle Scholar
  86. 86.
    Morgner, N.; Kleinschroth, T.; Barth, H. D.; Ludwig, B.; Brutschy, B. A Novel Approach to Analyze Membrane Proteins by Laser Mass Spectrometry: From Protein Subunits to the Integral Complex. J. Am. Soc. Mass Spectrom. 2007, 18, 1429–1438.CrossRefGoogle Scholar
  87. 87.
    Hanna, J.; Finley, D. A Proteasome for All Occasions. FEBS Lett. 2007, 581, 2854–2861.CrossRefGoogle Scholar
  88. 88.
    Hartwell, L. H.; Hopfield, J. J.; Leibler, S.; Murray, A. W. From Molecular to Modular Cell Biology. Nature. 1999, 402, C47-C52.CrossRefGoogle Scholar
  89. 89.
    Alberts, B. The Cell as a Collection of Protein Machines: Preparing the Next Generation of Molecular Biologists. Cell. 1998, 92, 291–294.CrossRefGoogle Scholar
  90. 90.
    Glickman, M. H.; Raveh, D. Proteasome Plasticity. FEBS Lett. 2005, 579, 3214–3223.CrossRefGoogle Scholar
  91. 91.
    Wei, N.; Serino, G.; Deng, X. W. The COP9 Signalosome: More Than a Protease. Trends Biochem. Sci. 2008, 33, 592–600.CrossRefGoogle Scholar
  92. 92.
    Gonzalez, C. M.; Griffey, S. M.; Naydan, D. K.; Flores, E.; Cepeda, R.; Cattaneo, G.; Madewell, B. R. Canine Transmissible Venereal Tumor: A Morphological and Immunohistochemical Study of 11 Tumors in Growth Phase and During Regression After Chemotherapy. J. Comp. Pathol. 2000, 122, 241–248.CrossRefGoogle Scholar
  93. 93.
    Kitova, E. N.; Kitov, P. I.; Bundle, D. R.; Klassen, J. S. The Observation of Multivalent Complexes of Shiga-Like Toxin with Globotriaoside and the Determination of Their Stoichiometry by Nanoelectrospray Fourier-Transform Ion Cyclotron Resonance Mass Spectrometry. Glycobiology 2001, 11, 605–611.CrossRefGoogle Scholar
  94. 94.
    Robinson, C. V.; Chung, E. W.; Kragelund, B. B.; Knudsen, J.; Aplin, R. T.; Poulsen, F. M.; Dobson, C. M. Probing the Nature of Noncovalent Interactions by Mass Spectrometry: A Study of Protein-CoA Ligand Binding and Assembly. J. Am. Chem. Soc. 1996, 118, 8646–8653.CrossRefGoogle Scholar
  95. 95.
    Rupp, B. High-Throughput Crystallography at an Affordable Cost: The TB Structural Genomics Consortium Crystallization Facility. Acc. Chem. Res. 2003, 36, 173–181.CrossRefGoogle Scholar
  96. 96.
    Service, R. F. Structural Biology: Robots Enter the Race to Analyze Proteins. Science. 2001, 292, 187–188.CrossRefGoogle Scholar

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© American Society for Mass Spectrometry 2010

Authors and Affiliations

  1. 1.Department of Biological ChemistryWeizmann Institute of ScienceRehovotIsrael

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