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Top-Down Proteomics Mass Spectrometry

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Top-Down Proteomics Mass Spectrometry Top-Down Proteomics Mass Spectrometry University of Florence, March 19, 2010 “Bottom-Up” of proteins : Before MS, slash, bash, smash into peptides. 2010: MS Proteomics >90% bottom-up Fred W. McLafferty, Cornell University Top-Down versus Bottom-Up Protein Characterization by Tandem High-Resolution Mass Spectrometry Kelleher, N. L, Lin, H. Y, Valaskovic, G. A, Aaserud, D. J, Fridriksson, E. K, McLafferty, F. W. J. Am. Chem. Soc. 1999, 121, 806-812 Carbonic Anhydrase Calculated Mr = 29023.7-17 2831.7 -1 2960.6 -1 7601.5 -4 15191 -2 15319.2 -10 6103.5 -3 7247.3, 7146.3, 7045.2 -4 4614.4 -2 10704.9 -8 4950.9 -2 20270.2 -12 8754.1 -5 20972.6 -12 21422.8 -13 4614.4 -2 15319.2 -10 b135 -b134, 128.01 : Q, -0.05 7601.5 -4 10704.9 -8 4950.9 -2 Da 29024.3 -17 6103.5 -3 29024.2 -17 y63 -y62, 101.04:T, -0.01 7601.5 -4 y62 -y61, 101.11: T, +0.06 29024.3 -17 Cornell never has BUT- done Bottom-Up Top-Down began before McLafferty J. J. Thompson, 1913 MS of Linear Molecules (1958) Mycoserosic acid (1 µg) from tubercle bacilli Showing four methyl branch positions Rearrangement 13 28 R. Ryhage, E. Stenhagen J. Lipid Res. 1960, 1, 361. 1 microgram! 14 28 14 28 Top-Down Units: CH2, 14 Da; CH(CH3), 28 Da Problem: MS of Nonlinear Molecules Clivonine Hippeastrine Solution #1: Study Klaus Biemann’s papers Not a Linear Molecule? Rearrangement? Databases of Electron Ionization Mass Spectra Wiley 1969 Registry of Mass Spectral Data, 6.8K spectra Stenhagen, Abrahamsson, McLafferty, Editors Wiley 2009 Registry, 9th Edition, 660K spectra NIST 2008 Edition, 220K spectra Wiley 2009 Registry with NIST, 9th Edition, 796K spectra 746K searchable chemical structures 667K different chemical compounds Probability Based Matching: 796K in <1 s Electrospray Ionization - John Fenn 1-3 kV ESI is Really Gentle - BUT Is the native conformation retained? Molecular Weight, Specificity Bovine Casein in Mozzarella Cheese Legal limit 5%, used “Tasters” 1989 Electrospray Ionization MS, 1989 3 isoforms Detect 1% Bovine! Amount of data ~ “peak capacity” = Width (m/z range) x Resolving power Fourier-Transform Ion Cyclotron Resonance EquippedFragmentation with MassMultiple Spectrometer Techniques MS/MS Techniques in FTMS Comisarow and Marshall Multiple MS/MS techniques Orbitrap, no magnet, ECD “Middle-Down” MS Electron Capture Dissociation (electron2 Electron filament andGuns emitter) 1. ECD 2. Hot e, Activation Nanospray Superconducting ESI source IRMPD Magnet 6 T Laser ----- IR multiphoton activation BIRD Blackbody IR Collisionally “In-beam” Nozzle-skimmer Capillary activation activated activation activation denaturation CAD dissociation CAD Also Tunable IR Laser for IR Photofragment Spectroscopy Electrospray Ionization of Bovine β-Casein 3 Variants, 5 Phosphorylations Isotopic clusters A1 = 24007.2 -14 13C, 15N, 18O, 34S etc. 14 Da higher mass than A2 = 23968.2 -14 monoisotopic peak Mass of highest Resolving Power 105 abundance peak A + Na (theoretical fit) 1 + 21H+ A + Na 2 B = 24077.2 -14 Electrospray Ionization “Bottom Up”: trypsin digest, MS of peptides Molec. Cellular Proteomics 2003, 2, 1253-1260. IDENTIFICATION DNA predicted proteins: CAD Characterization of a Protein Mr = 16309.7 “Identification” by Bottom Up C “Characterization” By Top Down Top-Down: 1) Select protein by MS/MS. 2) Don’t throw away connectivity info. Units: Amino Acids X X X X BUT completeLinear sequence Molecule, or exact Cleave PTM positioningOne Bond demands a fragment mass(neglecting from each interresidue ion chemistry) bond cleavage – and weakest bonds preferentially cleaved Chemistry of The Mass Spectrometry of Large Molecules Electron ionization – requires vaporization Removes an electron, yields Odd-Electron Ion- More easily dissociated, less rearrangement MS requires charged species- Chemical Ionization, Plasma Desorption, Fast Atom Bombardment, Matrix Assisted Laser Desorption Ionization, Electrospray Ionization But – these produce mainly Even-Electron Ions! New Chemical Reaction Needed M+ M+• How? M+ + electron M+• Energetic Dissociation: CAD, IRMPD, BIRD, SID Electron Capture Dissociation (with FTMS) Zubarev, R. A.; Kelleher, N. L.; McLafferty, F. W. JACS, 1998, 120, 3265 ~6 eV neutralization energy N C Electron Transfer Dissociation (Bottom-Up!) Syka, J. E. P.; Coon, J. J.; Schroeder, M. J; Shabanowitz, J.; Hunt, D. F. PNAS, 2004, 101, 9528. Deamidation of Reduced Ribonuclease A ─NH →─OH, Exptl: 13,689.3-8 2 Calcd: 13,689.3-8 ∆ = +1 Da Zabrouskov, Han, Welker, Zhai, Lin, van Wijk, Scheraga, McLafferty, Biochemistry 2006, 45, 987-992. MS/MS Method to measure age? Deamidation of RNase A Only Asn67 found since 1968 Gln74 Asn34 Asn71,Asn94 Asn67 Electron Capture Nonergodic Dissociation <10-12 s, before energy randomization • Negligible time for rearrangement • stops H/D scrambling (D atoms on exposed conformers) • Most interresidue bonds can be cleaved (250/258) e- neutralization energy >> bond dissociation energy • Fragment ion has N- or C-terminus, identifiable by CAD, ECD IRMPD Important for de novo sequencing ••Side Side chain chain posttranslationalposttranslational modifications modifications are are stable stable 26 Phophorylation Sites in β-Casein by Plasma-ECD Phosphorylated126/208 Sites ininterresidue β-casein cleavages(24.9 kDa) by AI-ECD ya//yb /zc / 209 R E L E E L N V P G E I V E SSPPP L S SP E 20 189 E S I T R I N K K I E K F Q SP E E Q Q Q 40 169 T E D E L Q D K I H P F A Q T Q S L V Y 60 149 P F P G P I P N S L P Q N I P P L T Q T 80 129 PVVV PPFLQPEVMGVSKVKE 100 109 A M A P K H K E M P F P K Y P V E P F T 120 89 E S Q S L T L T D V E N L H L P L P L L 140 69 QSWMHQPHQPLPPTVMFPPQ 160 49 S V L S L S Q S K V L P V P Q K A V P Y 180 29 PQRDMPI QAFL LYQEPVLGP 200 9 V R G P F P I I V 209 b a c 129/208Sze, S. K.; bonds Ge, Y.; cleaved Oh, H. B.; total McLafferty, F. W. CAD ECD Anal. Chem. 2003, 75, 1599-1603. y z . y Electron Capture Nonergodic Dissociation <10-12 s, before energy randomization • Negligible time for rearrangement • stops H/D scrambling (D atoms on exposed conformers) • Most interresidue bonds can be cleaved (250/258) e- neutralization energy >> bond dissociation energy • Fragment ion has N- or C-terminus, identifiable by CAD, ECD IRMPD Important for de novo sequencing • Side chain posttranslational modifications are stable • Tertiary noncovalent bonds not cleaved – ECD cleavage sites depend on conformation! Horn, Ge, McLafferty, Activated Ion Electron Capture Dissociation for Mass Spectral Sequencing of Larger (42 kDa) Proteins, Anal. Chem. 2000, 72, 4778-4784. Top Down Characterization of Carbonic Anhydrase "Top Down" of Bovine Carbonic Anhydrase 3.0 MW: calculated, 29024.7 -18, experimental, 29024.3 -18 ECD Mol. Wt.: calculated, 29024.7-18;-18, experimental, 29024.3-18-18 512 Fragment ion mass values, 183/258 interresidue bonds Fragment ions from residues 10-30 show 45 errors of -1 Da Fragment ions from residues 10-30 show 45 errors* * of -1 Da a• Protein Data Base: 10 31 b 2.5 Bovine (1) SHHWGYGKHDGPZHWHKDFPIANGERQSPVNIDTK c Sheep SHHWGYGEHNGPEHWHKDFPIADGERQSPVDIDTK y z• Human SHHWGYGKHNGPEHWHKDFPIAKGERQSPVDIDTH 2.0 ECD(2) SHHWGYGKHNGPZHWHKDFPIANGERQSPVDIDTK (1)Ref: Beu, Kelleher, S.; Senko, N.L.; Lin, M. H.Y.; W.; Valaskovic, Quinn, J. G.A.; P.; McLafferty,Aaserud, D.J.; F. Fridriksson, W. JASMS E.K.;1993, 4, 190 (2) Sze, McLafferty, S. K.; F.W.,Ge, Y.; J. Am.Oh, Chem. H. B.; Soc. McLafferty, 1999, 121, F. W.806-812. Anal. Chem. 2003, 75, 1599 O= 1.5 * Product Ions Product Asp (D): -C-O- Σ -1 Da %, %, vs. * O= Asn (N): H 1.0 -C-N- *** * *** 0.5 ** ** * * 0.0 20 40 60 80 100 120 140 160 180 200 220 240 Residue Automated MS Proteomics Bottom-Up: 7000 proteins identified, M. Mann, et al., Nat. Methods, 2009, 6, 359. Top-Down: Neil Kelleher, University of Illinois Off Line Separation: 1D Gel, RP LC, collect fractions MS: ESI, Octopole ion concentration, exact mass FTMS MS/MS: CAD, ECD Data Reduction: THRASH, ProSight PTM vs. predicted proteins Anal. Chem. 2004, 76, 197A-203A. Top Down in Chromatin Biology Nuclear membrane Chromatin fiber Interphase Chromatin fiber nucleus (30 nm dia.) Prof. Neil H1 Nucleosomes Kelleher, U. of Illinois H1 Trans‐acting }factors Nuclear DNA pore Nuclear matrix Top Down has provided the definitive list of histone isoforms present in yeast and human cells. What about a possible combinatorial “Histone Code”? Histone H3: Ac Ac Me1 Me1 Ac Ac P Me1-3 Me1-3 P P Ac Ac P Ac Me1-3 P P Me1-3 ARTKQTARKSTGGKAPRKQLATKAARKSAPSTGGVKKPH… TARKSTGGKacAPRKQL YRPGTVALR Kme2SphosTGGKacAPR TK QTAR me2 Kme3SAPSTGGVKme1KPHR KacQLATKacAAR KAARKme1SAPSTGGVKK c P Me Me P A Ac P Ac Me P AR T K QTAR KS TGGKAPRKQLA TKAAR KSAP… 3 4 9 10 14 18 22 23 27 28 Can we use mass spectrometry to identify modifications on Single Forms that occur concurrently? High Resolution MS/MS on Histone H3 “Middle-Down” MS Proteomics B.A. Garcia, J.J. Pesavento, C.A. Mizzen and N.L. Kelleher, Nature Methods, 2007, 4, 487. M. Mann, N. L. Kelleher, PNAS, 2008, 105, 18132-18138.. Effect of Electrospray on Protein Conformation Electrospray retains biological activity! Ions mass- separated in instrument, ACTIVE. Virus: Gary Siuzdak. Soft landing: Graham Cooks, Vicki Wysocki Large (>0.5 MDa) Protein Complexes: Carol Robinson: Intraprotein noncovalent bonds stable.
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