Structural Characterization of Monomers and Oligomers of D-Amino Acid-Containing Peptides Using T-Wave Ion Mobility Mass Spectrometry

  • Xueqin Pang
  • Chenxi Jia
  • Zhengwei Chen
  • Lingjun Li
Focus: 31st Asilomar Conference, Native MS-based Structural Biology: Research Article

Abstract

The D-residues are crucial to biological function of D-amino acid containing peptides (DAACPs). Previous ion mobility mass spectrometry (IM-MS) studies revealing oligomerization patterns of amyloid cascade demonstrated conversion from native soluble unstructured assembly to fibril ß-sheet oligomers, which has been implicated in amyloid diseases, such as Alzheimer’s disease and type 2 diabetes. Although neuropeptides are typically present at very low concentrations in circulation, their local concentrations could be much higher in large dense core vesicles, forming dimers or oligomers. We studied the oligomerization of protonated and metal-adducted achatin I and dermorphin peptide isomers with IM-MS. Our results suggested that dimerization, oligomerization, and metal adduction augment the structural differences between D/L peptide isomers compared to protonated monomers. Dimers and oligomers enhanced the structural differences between D/L peptide isomers in both aqueous and organic solvent system. Furthermore, some oligomer forms were only observed for either D- or L-isomers, indicating the importance of chiral center in oligomerization process. The oligomerization patterns of D/L isomers appear to be similar. Potassium adducts were detected to enlarge the structural differences between D/L isomers.

Graphical Abstract

Keywords

Ion mobility mass spectrometry IM-MS D-amino acid containing peptides DAACPs Native state Organic solvent Monomer Dimer Oligomer Oligomerization pattern Metal adducts Collision cross-section CCS Conformational differences 

References

  1. 1.
    Montecucchi, P.C., de Castiglione, R., Piani, S., Gozzini, L., Erspamer, V.: Amino acid composition and sequence of dermorphin, a novel opiate-like peptide from the skin of Phyllomedusa sauvagei. Int. J. Pept. Protein Res. 17, 275–283 (1981)CrossRefGoogle Scholar
  2. 2.
    Bai, L., Sheeley, S., Sweedler, J.V.: Analysis of endogenous D-amino acid-containing peptides in metazoa. Bioanal. Rev. 1, 7–24 (2009)CrossRefGoogle Scholar
  3. 3.
    Soyez, D., Van Herp, F., Rossier, J., Le Caer, J.P., Tensen, C.P., Lafont, R.: Evidence for a conformational polymorphism of invertebrate neurohormones. D-amino acid residue in crustacean hyperglycemic peptides. J. Biol. Chem. 269, 18295–18298 (1994)Google Scholar
  4. 4.
    Yasuda, A., Yasuda, Y., Fujita, T., Naya, Y.: Characterization of crustacean hyperglycemic hormone from the crayfish (Procambarus clarkii): multiplicity of molecular forms by stereoinversion and diverse functions. Gen. Comp. Endocrinol. 95, 387–398 (1994)CrossRefGoogle Scholar
  5. 5.
    Kamatani, Y., Minakata, H., Kenny, P.T., Iwashita, T., Watanabe, K., Funase, K., Sun, X.P., Yongsiri, A., Kim, K.H., Novales-Li, P., Novales, T.N., Lanapi, C.G., Takeuchi, H., Nomoto, K.: Achatin-I, an endogenous neuroexcitatory tetrapeptide from Achatina fulica Ferussac containing a D-amino acid residue. Biochem. Biophys. Res. Commun. 160, 1015–1020 (1989)CrossRefGoogle Scholar
  6. 6.
    Yasuda-Kamatani, Y., Kobayashi, M., Yasuda, A., Fujita, T., Minakata, H., Nomoto, K., Nakamura, M., Sakiyama, F.: A novel D-amino acid-containing peptide, fulyal, coexists with fulicin gene-related peptides in Achatina atria. Peptides 18, 347–354 (1997)CrossRefGoogle Scholar
  7. 7.
    Morishita, F., Nakanishi, Y., Kaku, S., Furukawa, Y., Ohta, S., Hirata, T., Ohtani, M., Fujisawa, Y., Muneoka, Y., Matsushima, O.: A novel D-amino-acid-containing peptide isolated from Aplysia heart. Biochem. Biophys. Res. Commun. 240, 354–358 (1997)CrossRefGoogle Scholar
  8. 8.
    Heck, S.D., Kelbaugh, P.R., Kelly, M.E., Thadeio, P.F., Saccomano, N.A., Stroh, J.G., Volkmann, R.A.: Disulfide bond assignment of omega-Agatoxin-Ivb and Omega-Agatoxin-Ivc—Discovery of a D-serine residue in omega-Agatoxin-Ivb. J. Am. Chem. Soc. 116, 10426–10436 (1994)CrossRefGoogle Scholar
  9. 9.
    Mor, A., Delfour, A., Sagan, S., Amiche, M., Pradelles, P., Rossier, J., Nicolas, P.: Isolation of dermenkephalin from amphibian skin, a high-affinity delta-selective opioid heptapeptide containing a D-amino acid residue. FEBS Lett. 255, 269–274 (1989)CrossRefGoogle Scholar
  10. 10.
    Kreil, G., Barra, D., Simmaco, M., Erspamer, V., Erspamer, G.F., Negri, L., Severini, C., Corsi, R., Melchiorri, P.: Deltorphin, a novel amphibian skin peptide with high selectivity and affinity for delta opioid receptors. Eur. J. Pharmacol. 162, 123–128 (1989)CrossRefGoogle Scholar
  11. 11.
    Barra, D., Mignogna, G., Simmaco, M., Pucci, P., Severini, C., Falconieri-Erspamer, G., Negri, L., Erspamer, V.: [D-Leu2]deltorphin, a 17 amino acid opioid peptide from the skin of the Brazilian hylid frog, Phyllomedusa burmeisteri. Peptides 15, 199–202 (1994)CrossRefGoogle Scholar
  12. 12.
    Torres, A.M., Menz, I., Alewood, P.F., Bansal, P., Lahnstein, J., Gallagher, C.H., Kuchel, P.W.: D-amino acid residue in the C-type natriuretic peptide from the venom of the mammal, Ornithorhynchus anatinus, the Australian platypus. FEBS Lett. 524, 172–176 (2002)CrossRefGoogle Scholar
  13. 13.
    Torres, A.M., Tsampazi, C., Geraghty, D.P., Bansal, P.S., Alewood, P.F., Kuchel, P.W.: D-amino acid residue in a defensin-like peptide from platypus venom: effect on structure and chromatographic properties. Biochem. J. 391, 215–220 (2005)CrossRefGoogle Scholar
  14. 14.
    Shikata, Y., Watanabe, T., Teramoto, T., Inoue, A., Kawakami, Y., Nishizawa, Y., Katayama, K., Kuwada, M.: Isolation and characterization of a peptide isomerase from funnel web spider venom. J. Biol. Chem. 270, 16719–16723 (1995)CrossRefGoogle Scholar
  15. 15.
    Soyez, D., Vanherp, F., Rossier, J., Lecaer, J.P., Tensen, C.P., Lafont, R.: Evidence for a conformational polymorphism of invertebrate neurohormones—D-amino-acid residue in crustacean hyperglycemic peptides. J. Biol. Chem. 269, 18295–18298 (1994)Google Scholar
  16. 16.
    Tao, Y., Julian, R.R.: Identification of amino acid epimerization and isomerization in crystallin proteins by tandem LC-MS. Anal. Chem. 86, 9733–9741 (2014)CrossRefGoogle Scholar
  17. 17.
    Sheeley, S.A., Miao, H., Ewing, M.A., Rubakhin, S.S., Sweedler, J.V.: Measuring D-amino acid-containing neuropeptides with capillary electrophoresis. Analyst 130, 1198–1203 (2005)CrossRefGoogle Scholar
  18. 18.
    Cooks, R.G., Wong, P.S.H.: Kinetic method of making thermochemical determinations: Advances and applications. Acc. Chem. Res. 31, 379–386 (1998)CrossRefGoogle Scholar
  19. 19.
    Tao, W.A., Zhang, D.X., Nikolaev, E.N., Cooks, R.G.: Copper(II)-assisted enantiomeric analysis of D,L-amino acids using the kinetic method: chiral recognition and quantification in the gas phase. J. Am. Chem. Soc. 122, 10598–10609 (2000)CrossRefGoogle Scholar
  20. 20.
    Bai, L., Romanova, E.V., Sweedler, J.V.: Distinguishing endogenous D-amino acid-containing neuropeptides in individual neurons using tandem mass spectrometry. Anal. Chem. 83, 2794–2800 (2011)CrossRefGoogle Scholar
  21. 21.
    Adams, C.M., Kjeldsen, F., Zubarev, R.A., Budnik, B.A., Haselmann, K.F.: Electron capture dissociation distinguishes a single D-amino acid in a protein and probes the tertiary structure. J. Am. Soc. Mass Spectrom. 15, 1087–1098 (2004)CrossRefGoogle Scholar
  22. 22.
    Tao, Y., Quebbemann, N.R., Julian, R.R.: Discriminating D-amino acid-containing peptide epimers by radical-directed dissociation mass spectrometry. Anal. Chem. 84, 6814–6820 (2012)CrossRefGoogle Scholar
  23. 23.
    Jia, C., Lietz, C.B., Yu, Q., Li, L.: Site-specific characterization of D-amino acid-containing peptide epimers by ion mobility spectrometry. Anal. Chem. 86, 2972–2981 (2014)CrossRefGoogle Scholar
  24. 24.
    Bleiholder, C., Dupuis, N.F., Wyttenbach, T., Bowers, M.T.: Ion mobility-mass spectrometry reveals a conformational conversion from random assembly to β-sheet in amyloid fibril formation. Nat. Chem. 3, 172–177 (2011)CrossRefGoogle Scholar
  25. 25.
    Smith, D.P., Radford, S.E., Ashcroft, A.E.: Elongated oligomers in β2-microglobulin amyloid assembly revealed by ion mobility spectrometry-mass spectrometry. Proc. Natl. Acad. Sci. U. S. A. 107, 6794–6798 (2010)CrossRefGoogle Scholar
  26. 26.
    Bernstein, S.L., Dupuis, N.F., Lazo, N.D., Wyttenbach, T., Condron, M.M., Bitan, G., Teplow, D.B., Shea, J.E., Ruotolo, B.T., Robinson, C.V., Bowers, M.T.: Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease. Nat. Chem. 1, 326–331 (2009)CrossRefGoogle Scholar
  27. 27.
    Wyttenbach, T., Pierson, N.A., Clemmer, D.E., Bowers, M.T.: Ion mobility analysis of molecular dynamics. Annu. Rev. Phys. Chem. 65, 175–196 (2014)CrossRefGoogle Scholar
  28. 28.
    Chiti, F., Dobson, C.M.: Amyloid formation by globular proteins under native conditions. Nat. Chem. Biol. 5, 15–22 (2009)CrossRefGoogle Scholar
  29. 29.
    Eisenberg, D., Nelson, R., Sawaya, M.R., Balbirnie, M., Sambashivan, S., Ivanova, M.I., Madsen, A.O., Riekel, C.: The structural biology of protein aggregation diseases: fundamental questions and some answers. Acc. Chem. Res. 39, 568–575 (2006)CrossRefGoogle Scholar
  30. 30.
    Haass, C., Selkoe, D.J.: Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nat. Rev. Mol. Cell Biol. 8, 101–112 (2007)CrossRefGoogle Scholar
  31. 31.
    Hrdina, P.D., Siegel G.J., Agranoff B.W., Albers R.W., Fisher S.K., Uhler M.D.: Basic neurochemistry: molecular, cellular, and medical aspects, 6th edition. Lippincott-Raven: Philadelphia (1999) Available at: http://www.ncbi.nlm.nih.gov/books/NBK20385/. Accessed 21 June 2016
  32. 32.
    Kuffler, S.W., Yoshikami, D.: The number of transmitter molecules in a quantum: an estimate from iontophoretic application of acetylcholine at the neuromuscular synapse. J. Physiol. 251, 465–482 (1975)CrossRefGoogle Scholar
  33. 33.
    Wightman, R.M., Jankowski, J.A., Kennedy, R.T., Kawagoe, K.T., Schroeder, T.J., Leszczyszyn, D.J., Near, J.A., Diliberto Jr., E.J., Viveros, O.H.: Temporally resolved catecholamine spikes correspond to single vesicle release from individual chromaffin cells. Proc. Natl. Acad. Sci. U. S. A. 88, 10754–10758 (1991)CrossRefGoogle Scholar
  34. 34.
    Pothos, E.N., Davila, V., Sulzer, D.: Presynaptic recording of quanta from midbrain dopamine neurons and modulation of the quantal size. J. Neurosci. 18, 4106–4118 (1998)Google Scholar
  35. 35.
    Sawaya, M.R., Sambashivan, S., Nelson, R., Ivanova, M.I., Sievers, S.A., Apostol, M.I., Thompson, M.J., Balbirnie, M., Wiltzius, J.J., McFarlane, H.T., Madsen, A.O., Riekel, C., Eisenberg, D.: Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature 447, 453–457 (2007)CrossRefGoogle Scholar
  36. 36.
    Nelson, R., Sawaya, M.R., Balbirnie, M., Madsen, A.O., Riekel, C., Grothe, R., Eisenberg, D.: Structure of the cross-beta spine of amyloid-like fibrils. Nature 435, 773–778 (2005)CrossRefGoogle Scholar
  37. 37.
    Nelson, R., Eisenberg, D.: Recent atomic models of amyloid fibril structure. Curr. Opin. Struct. Biol. 16, 260–265 (2006)CrossRefGoogle Scholar
  38. 38.
    Bush, M.F., Campuzano, I.D., Robinson, C.V.: Ion mobility mass spectrometry of peptide ions: effects of drift gas and calibration strategies. Anal. Chem. 84, 7124–7130 (2012)CrossRefGoogle Scholar
  39. 39.
    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. 3, 1139–1152 (2008)CrossRefGoogle Scholar
  40. 40.
    Shvartsburg, A.A., Smith, R.D.: Fundamentals of traveling wave ion mobility spectrometry. Anal. Chem. 80, 9689–9699 (2008)CrossRefGoogle Scholar
  41. 41.
    Lanucara, F., Holman, S.W., Gray, C.J., Eyers, C.E.: The power of ion mobility-mass spectrometry for structural characterization and the study of conformational dynamics. Nat. Chem. 6, 281–294 (2014)CrossRefGoogle Scholar
  42. 42.
    Zhong, Y., Hyung, S.J., Ruotolo, B.T.: Characterizing the resolution and accuracy of a second-generation traveling-wave ion mobility separator for biomolecular ions. Analyst 136, 3534–3541 (2011)CrossRefGoogle Scholar
  43. 43.
    Feinstein, H.E., Benbow, S.J., LaPointe, N.E., Patel, N., Ramachandran, S., Do, T.D., Gaylord, M.R., Huskey, N.E., Dressler, N., Korff, M., Quon, B., Cantrell, K.L., Bowers, M.T., Lal, R., Feinstein, S.C.: Oligomerization of the microtubule-associated protein tau is mediated by its N-terminal sequences: implications for normal and pathological tau action. J. Neurochem. 137, 939–954 (2016)CrossRefGoogle Scholar
  44. 44.
    Economou, N.J., Giammona, M.J., Do, T.D., Zheng, X., Teplow, D.B., Buratto, S.K., Bowers, M.T.: Amyloid β-protein assembly and Alzheimer's disease: dodecamers of Abeta42, but not of Abeta40, seed fibril formation. J. Am. Chem. Soc. 138, 1772–1775 (2016)CrossRefGoogle Scholar
  45. 45.
    Schmidt, M., Rohou, A., Lasker, K., Yadav, J.K., Schiene-Fischer, C., Fandrich, M., Grigorieff, N.: Peptide dimer structure in an Abeta(1-42) fibril visualized with cryo-EM. Proc. Natl. Acad. Sci. U. S. A. 112, 11858–11863 (2015)CrossRefGoogle Scholar

Copyright information

© American Society for Mass Spectrometry 2016

Authors and Affiliations

  • Xueqin Pang
    • 1
  • Chenxi Jia
    • 1
    • 2
  • Zhengwei Chen
    • 3
  • Lingjun Li
    • 1
    • 3
    • 4
  1. 1.School of PharmacyUniversity of Wisconsin-MadisonMadisonUSA
  2. 2.National Center for Protein Sciences-Beijing, Beijing Proteome Research Center, State Key Laboratory of ProteomicsBeijing Institute of Radiation MedicineBeijingChina
  3. 3.Department of ChemistryUniversity of Wisconsin-MadisonMadisonUSA
  4. 4.School of Life SciencesTianjin UniversityTianjinChina

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