Top-down Proteomics: Technology Advancements and Applications to Heart Diseases

ABSTRACT Introduction: Heart diseases are a leading cause of morbidity and mortality for both men and women worldwide, and impose significant economic burdens on the healthcare systems. Despite substantial effort over the last several decades, the molecular mechanisms underlying diseases of the heart remain poorly understood. Areas covered: Altered protein post-translational modifications (PTMs) and protein isoform switching are increasingly recognized as important disease mechanisms. Top-down high-resolution mass spectrometry (MS)-based proteomics has emerged as the most powerful method for the comprehensive analysis of PTMs and protein isoforms. Here, we will review recent technology developments in the field of top-down proteomics, as well as highlight recent studies utilizing top-down proteomics to decipher the cardiac proteome for the understanding of the molecular mechanisms underlying diseases of the heart. Expert commentary: Top-down proteomics is a premier method for the global and comprehensive study of protein isoforms and their PTMs, enabling the identification of novel protein isoforms and PTMs, characterization of sequence variations, and quantification of disease-associated alterations. Despite significant challenges, continuous development of top-down proteomics technology will greatly aid the dissection of the molecular mechanisms underlying diseases of the hearts for the identification of novel biomarkers and therapeutic targets.

[1]  Carol V Robinson,et al.  Mass spectrometry of intact membrane protein complexes , 2013, Nature Protocols.

[2]  Aldons J. Lusis,et al.  A thematic review series: systems biology approaches to metabolic and cardiovascular disorders , 2006, Journal of Lipid Research.

[3]  Ying Ge,et al.  Augmented Phosphorylation of Cardiac Troponin I in Hypertensive Heart Failure* , 2011, The Journal of Biological Chemistry.

[4]  Erik G Marklund,et al.  Bayesian deconvolution of mass and ion mobility spectra: from binary interactions to polydisperse ensembles. , 2015, Analytical chemistry.

[5]  Ying Ge,et al.  Top-down Proteomics Reveals Concerted Reductions in Myofilament and Z-disc Protein Phosphorylation after Acute Myocardial Infarction* , 2014, Molecular & Cellular Proteomics.

[6]  A. Risco,et al.  New Insights into the p38γ and p38δ MAPK Pathways , 2011, Journal of signal transduction.

[7]  Richard D. LeDuc,et al.  Mapping Intact Protein Isoforms in Discovery Mode Using Top Down Proteomics , 2011, Nature.

[8]  L. M. Smith,et al.  A mechanical nanomembrane detector for time-of-flight mass spectrometry. , 2011, Nano letters.

[9]  Jared B Shaw,et al.  Complete protein characterization using top-down mass spectrometry and ultraviolet photodissociation. , 2013, Journal of the American Chemical Society.

[10]  J. Whitelegge.  Intact protein mass spectrometry and top-down proteomics , 2013, Expert review of proteomics.

[11]  A. Alpert,et al.  Effective Protein Separation by Coupling Hydrophobic Interaction and Reverse Phase Chromatography for Top-down Proteomics , 2014, Analytical chemistry.

[12]  J. V. Van Eyk,et al.  Role of chromatographic techniques in proteomic analysis. , 2005, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[13]  P. Tombe.  Myosin Binding Protein C in the Heart , 2006 .

[14]  M. Mann,et al.  Precision proteomics: The case for high resolution and high mass accuracy , 2008, Proceedings of the National Academy of Sciences.

[15]  Paul M Thomas,et al.  Top down proteomics of human membrane proteins from enriched mitochondrial fractions. , 2013, Analytical chemistry.

[16]  Ying Ge,et al.  New mass-spectrometry-compatible degradable surfactant for tissue proteomics. , 2015, Journal of proteome research.

[17]  M. Mann,et al.  Electrospray ionization for mass spectrometry of large biomolecules. , 1989, Science.

[18]  Masashi Narita,et al.  Quantitation and Identification of Thousands of Human Proteoforms below 30 kDa. , 2016, Journal of proteome research.

[19]  T. Drake,et al.  Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders. Proteomics approaches to the systems biology of cardiovascular diseases Published, JLR Papers in Press, October 25, 2006. , 2007, Journal of Lipid Research.

[20]  Ying Ge,et al.  Top‐down proteomics in health and disease: Challenges and opportunities , 2014, Proteomics.

[21]  S. A. McLuckey,et al.  Top‐down protein characterization facilitated by ion/ion reactions on a quadrupole/time of flight platform , 2010, Proteomics.

[22]  Paul M Thomas,et al.  Large-scale Top-down Proteomics of the Human Proteome: Membrane Proteins, Mitochondria, and Senescence* , 2013, Molecular & Cellular Proteomics.

[23]  Ying Ge,et al.  Top-down quantitative proteomics identified phosphorylation of cardiac troponin I as a candidate biomarker for chronic heart failure. , 2011, Journal of proteome research.

[24]  R. Aebersold,et al.  Mass spectrometry-based proteomics for systems biology. , 2012, Current opinion in biotechnology.

[25]  Ying Ge,et al.  Effective top-down LC/MS+ method for assessing actin isoforms as a potential cardiac disease marker. , 2015, Analytical chemistry.

[26]  J. Potter,et al.  Generation and Functional Characterization of Knock-in Mice Harboring the Cardiac Troponin I-R21C Mutation Associated with Hypertrophic Cardiomyopathy* , 2011, The Journal of Biological Chemistry.

[27]  G. Vladimirov,et al.  Dynamically Harmonized FT-ICR Cell with Specially Shaped Electrodes for Compensation of Inhomogeneity of the Magnetic Field. Computer Simulations of the Electric Field and Ion Motion Dynamics , 2012, Journal of The American Society for Mass Spectrometry.

[28]  R. Cooks,et al.  Orbitrap mass spectrometry: instrumentation, ion motion and applications. , 2008, Mass spectrometry reviews.

[29]  P. D. de Tombe,et al.  Integration of Cardiac Myofilament Activity and Regulation with Pathways Signaling Hypertrophy and Failure , 2000, Annals of Biomedical Engineering.

[30]  M. Mann,et al.  The Impact II, a Very High-Resolution Quadrupole Time-of-Flight Instrument (QTOF) for Deep Shotgun Proteomics* , 2015, Molecular & Cellular Proteomics.

[31]  Daniel S Spellman,et al.  Quantitative analysis of intact apolipoproteins in human HDL by top-down differential mass spectrometry , 2010, Proceedings of the National Academy of Sciences.

[32]  N. Kelleher,et al.  Quantitative analysis of modified proteins and their positional isomers by tandem mass spectrometry: human histone H4. , 2006, Analytical chemistry.

[33]  P. Pevzner,et al.  Deconvolution and Database Search of Complex Tandem Mass Spectra of Intact Proteins , 2010, Molecular & Cellular Proteomics.

[34]  D. Wemmer,et al.  Effects of buffer loading for electrospray ionization mass spectrometry of a noncovalent protein complex that requires high concentrations of essential salts , 2010, Journal of the American Society for Mass Spectrometry.

[35]  R. Solaro,et al.  Why does troponin I have so many phosphorylation sites? Fact and fancy. , 2010, Journal of molecular and cellular cardiology.

[36]  Ying Ge,et al.  Top-down high-resolution mass spectrometry of cardiac myosin binding protein C revealed that truncation alters protein phosphorylation state , 2009, Proceedings of the National Academy of Sciences.

[37]  Jason C Rouse,et al.  Unit mass baseline resolution for an intact 148 kDa therapeutic monoclonal antibody by Fourier transform ion cyclotron resonance mass spectrometry. , 2011, Analytical chemistry.

[38]  G. Reid,et al.  Emerging methods in proteomics: top-down protein characterization by multistage tandem mass spectrometry. , 2007, The Analyst.

[39]  A. Cheema,et al.  Small Changes Huge Impact: The Role of Protein Posttranslational Modifications in Cellular Homeostasis and Disease , 2011, Journal of amino acids.

[40]  B. Chait.  Mass Spectrometry: Bottom-Up or Top-Down? , 2006, Science.

[41]  N. Kelleher,et al.  Decoding protein modifications using top-down mass spectrometry , 2007, Nature Methods.

[42]  M. Senko,et al.  Determination of monoisotopic masses and ion populations for large biomolecules from resolved isotopic distributions , 1995, Journal of the American Society for Mass Spectrometry.

[43]  Mark D. Huffman,et al.  AHA Statistical Update Heart Disease and Stroke Statistics — 2012 Update A Report From the American Heart Association WRITING GROUP MEMBERS , 2010 .

[44]  G. King,et al.  Activation of protein kinase C isoforms and its impact on diabetic complications. , 2010, Circulation research.

[45]  M. Mann,et al.  Proteomics to study genes and genomes , 2000, Nature.

[46]  C. Robinson,et al.  New vehicles allow detergent-free mass spectrometry of membrane protein complexes , 2013, Nature Methods.

[47]  Navdeep Jaitly,et al.  Decon2LS: An open-source software package for automated processing and visualization of high resolution mass spectrometry data , 2009, BMC Bioinformatics.

[48]  Michael Karas,et al.  Ion formation in MALDI: the cluster ionization mechanism. , 2003, Chemical reviews.

[49]  L. F. Waanders,et al.  Top-down quantitation and characterization of SILAC-labeled proteins , 2007, Journal of the American Society for Mass Spectrometry.

[50]  Deyang Yu,et al.  Top‐down mass spectrometry of cardiac myofilament proteins in health and disease , 2014, Proteomics. Clinical applications.

[51]  R. Ahrends,et al.  Application of metal-coded affinity tags (MeCAT): absolute protein quantification with top-down and bottom-up workflows by metal-coded tagging. , 2012, Analytical chemistry.

[52]  M. Nilges,et al.  Posttranslational Modification of Pili upon Cell Contact Triggers N. meningitidis Dissemination , 2011, Science.

[53]  G. Fonarow,et al.  Epidemiology and risk profile of heart failure , 2011, Nature Reviews Cardiology.

[54]  Ying Peng,et al.  MASH Suite Pro: A Comprehensive Software Tool for Top-Down Proteomics* , 2015, Molecular & Cellular Proteomics.

[55]  F. McLafferty,et al.  Top down characterization of larger proteins (45 kDa) by electron capture dissociation mass spectrometry. , 2002, Journal of the American Chemical Society.

[56]  Ying Ge,et al.  In vivo phosphorylation site mapping in mouse cardiac troponin I by high resolution top-down electron capture dissociation mass spectrometry: Ser22/23 are the only sites basally phosphorylated. , 2009, Biochemistry.

[57]  S. Silver,et al.  Heart Failure , 1937, The New England journal of medicine.

[58]  N. M. Karabacak,et al.  Sensitive and Specific Identification of Wild Type and Variant Proteins from 8 to 669 kDa Using Top-down Mass Spectrometry*S , 2009, Molecular & Cellular Proteomics.

[59]  Zachery R Gregorich,et al.  In-depth proteomic analysis of human tropomyosin by top-down mass spectrometry , 2013, Journal of Muscle Research and Cell Motility.

[60]  Yong-Bin Kim,et al.  ProSight PTM 2.0: improved protein identification and characterization for top down mass spectrometry , 2007, Nucleic Acids Res..

[61]  Ying S. Ting,et al.  Protein Identification Using Top-Down Spectra* , 2012, Molecular & Cellular Proteomics.

[62]  F. McLafferty,et al.  High-resolution electrospray mass spectra of large molecules , 1991 .

[63]  Igor A Kaltashov,et al.  Characterization of intact protein conjugates and biopharmaceuticals using ion-exchange chromatography with online detection by native electrospray ionization mass spectrometry and top-down tandem mass spectrometry. , 2015, Analytical chemistry.

[64]  H. Watkins,et al.  Cardiac Myosin Binding Protein C: Its Role in Physiology and Disease , 2004, Circulation research.

[65]  Carol V Robinson,et al.  Mass spectrometry of protein complexes: from origins to applications. , 2015, Annual review of physical chemistry.

[66]  Joe Carroll,et al.  Definition of the mitochondrial proteome by measurement of molecular masses of membrane proteins , 2006, Proceedings of the National Academy of Sciences.

[67]  Charles Ansong,et al.  Top-down proteomics reveals a unique protein S-thiolation switch in Salmonella Typhimurium in response to infection-like conditions , 2013, Proceedings of the National Academy of Sciences.

[68]  N. Kelleher,et al.  Top-down approaches for measuring expression ratios of intact yeast proteins using Fourier transform mass spectrometry. , 2006, Analytical chemistry.

[69]  J. C. Tran,et al.  Gel-eluted liquid fraction entrapment electrophoresis: an electrophoretic method for broad molecular weight range proteome separation. , 2008, Analytical chemistry.

[70]  J. C. Tran,et al.  Multiplexed size separation of intact proteins in solution phase for mass spectrometry. , 2009, Analytical chemistry.

[71]  J. C. Tran,et al.  Intact proteome fractionation strategies compatible with mass spectrometry , 2011, Expert review of proteomics.

[72]  D. C. Simpson,et al.  Proteomic profiling of intact proteins using WAX-RPLC 2-D separations and FTICR mass spectrometry. , 2007, Journal of proteome research.

[73]  Ying Ge,et al.  Deciphering modifications in swine cardiac troponin I by top-down high-resolution tandem mass spectrometry , 2010, Journal of the American Society for Mass Spectrometry.

[74]  Jun Ren,et al.  Sarcomeric protein isoform transitions in cardiac muscle: a journey to heart failure. , 2015, Biochimica et biophysica acta.

[75]  F. McLafferty,et al.  Unit resolution mass spectra of 112 kDa molecules with 3 Da accuracy , 1997 .

[76]  F. Pontén,et al.  Correlations between RNA and protein expression profiles in 23 human cell lines , 2009, BMC Genomics.

[77]  Zachery R Gregorich,et al.  Comprehensive assessment of chamber-specific and transmural heterogeneity in myofilament protein phosphorylation by top-down mass spectrometry. , 2015, Journal of molecular and cellular cardiology.

[78]  G. Ravenscroft,et al.  Investigation of changes in skeletal muscle α-actin expression in normal and pathological human and mouse hearts , 2010, Journal of Muscle Research and Cell Motility.

[79]  Ying Ge,et al.  Online Hydrophobic Interaction Chromatography-Mass Spectrometry for Top-Down Proteomics. , 2016, Analytical chemistry.

[80]  Steven B Marston,et al.  Modulation of thin filament activation by breakdown or isoform switching of thin filament proteins: physiological and pathological implications. , 2003, Circulation research.

[81]  Julian P Whitelegge,et al.  HPLC and mass spectrometry of intrinsic membrane proteins. , 2004, Methods in molecular biology.

[82]  A. Alpert.  Size Exclusion High-Performance Liquid Chromatography of Small Solutes , 1999 .

[83]  David A. Kass,et al.  Tackling heart failure in the twenty-first century , 2008, Nature.

[84]  Lloyd M. Smith,et al.  Mass spectrometric analysis of DNA mixtures: instrumental effects responsible for decreased sensitivity with increasing mass. , 2003, Analytical chemistry.

[85]  Makarov,et al.  Electrostatic axially harmonic orbital trapping: a high-performance technique of mass analysis , 2000, Analytical chemistry.

[86]  Ying Ge,et al.  Single amino acid sequence polymorphisms in rat cardiac troponin revealed by top–down tandem mass spectrometry , 2009, Journal of Muscle Research and Cell Motility.

[87]  F. McLafferty,et al.  Extending Top-Down Mass Spectrometry to Proteins with Masses Greater Than 200 Kilodaltons , 2006, Science.

[88]  F. McLafferty,et al.  Top‐down MS, a powerful complement to the high capabilities of proteolysis proteomics , 2007, The FEBS journal.

[89]  F. McLafferty,et al.  Electron capture dissociation for structural characterization of multiply charged protein cations. , 2000, Analytical chemistry.

[90]  T. Hunter.  The age of crosstalk: phosphorylation, ubiquitination, and beyond. , 2007, Molecular cell.

[91]  P. D. de Tombe.  Myosin binding protein C in the heart. , 2006, Circulation research.

[92]  J. Shabanowitz,et al.  Peptide and protein sequence analysis by electron transfer dissociation mass spectrometry. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[93]  P. Pevzner,et al.  Interpreting top-down mass spectra using spectral alignment. , 2008, Analytical chemistry.

[94]  Ying Ge,et al.  Top-down targeted proteomics for deep sequencing of tropomyosin isoforms. , 2013, Journal of proteome research.

[95]  Ying Ge,et al.  Three dimensional liquid chromatography coupling ion exchange chromatography/hydrophobic interaction chromatography/reverse phase chromatography for effective protein separation in top-down proteomics. , 2015, Analytical chemistry.

[96]  M. Mann,et al.  Proteomic analysis of post-translational modifications , 2003, Nature Biotechnology.

[97]  Ying Ge,et al.  Ultrahigh pressure fast size exclusion chromatography for top‐down proteomics , 2013, Proteomics.

[98]  Brian T Chait,et al.  Chemistry. Mass spectrometry: bottom-up or top-down? , 2006, Science.

[99]  Leonid Zamdborg,et al.  On the scalability and requirements of whole protein mass spectrometry. , 2011, Analytical chemistry.

[100]  Puneet Souda,et al.  Profiling of integral membrane proteins and their post translational modifications using high-resolution mass spectrometry. , 2011, Methods.

[101]  Ying Ge,et al.  Proteomics in heart failure: top-down or bottom-up? , 2014, Pflügers Archiv - European Journal of Physiology.

[102]  Ying Ge,et al.  Comprehensive Analysis of Protein Modifications by Top-Down Mass Spectrometry , 2011, Circulation. Cardiovascular genetics.

[103]  Lloyd M. Smith,et al.  Proteoform: a single term describing protein complexity , 2013, Nature Methods.

[104]  S. A. McLuckey,et al.  Ion parking during ion/ion reactions in electrodynamic ion traps. , 2002, Analytical chemistry.

[105]  Saša M. Miladinović,et al.  In-spray supercharging of peptides and proteins in electrospray ionization mass spectrometry. , 2012, Analytical chemistry.