Abstract
Human proteins can exist as multiple proteoforms with potential diagnostic or prognostic significance. MS top-down approaches are ideally suited for proteoforms identification because there is no prerequisite for a priori knowledge of the specific proteoform. One such top-down approach, termed mass spectrometric immunoassay utilizes antibody-derivatized microcolumns for rapid and contained proteoforms isolation and detection via MALDI-TOF MS. The mass spectrometric immunoassay can also provide quantitative measurement of the proteoforms through inclusion of an internal reference standard into the analytical sample, serving as normalizer for all sample processing and data acquisition steps. Reviewed here are recent developments and results from the application of mass spectrometric immunoassays for discovery of clinical correlations of specific proteoforms for the protein biomarkers RANTES, retinol binding protein, serum amyloid A and apolipoprotein C-III.
References
- 1 , Proteomics CfTD. Proteoform: a single term describing protein complexity. Nat. Methods 10(3), 186–187 (2013).
- 2 . Review: alternative splicing (AS) of genes as an approach for generating protein complexity. Curr. Genomics 14(3), 182–194 (2013).
- 3 . Molecular basis for population variation: from SNPs to SAPs. FEBS Lett. 586(18), 2841–2845 (2012).
- 4 . Identification and quantification of protein posttranslational modifications. Methods Enzymol. 463, 725–763 (2009).
- 5 2D gel proteomics: an approach to study age-related differences in protein abundance or isoform complexity in biological samples. Methods Mol. Biol. 371, 349–391 (2007).
- 6 Statistical analysis of variation in the human plasma proteome. J. Biomed. Biotechnol. 258494 (2010).
- 7 Considerations for powering a clinical proteomics study: Normal variability in the human plasma proteome. Proteomics Clin. Appl. 3(3), 394–407 (2009).
- 8 Age-related differences in plasma proteins: how plasma proteins change from neonates to adults. PLoS ONE 6(2), e17213 (2011).
- 9 . Decoding protein modifications using top-down mass spectrometry. Nat. Methods 4(10), 817–821 (2007).
- 10 . Comprehensive analysis of protein modifications by top-down mass spectrometry. Circ. Cardiovasc. Genet. 4(6), 711 (2011).
- 11 . Analysis of protein isoforms: can we do it better? Proteomics 12(19–20), 2937–2948 (2012).
- 12 . Identification and quantification of osteopontin splice variants in the plasma of lung cancer patients using immunoaffinity capture and targeted mass spectrometry. Biomarkers 17(2), 125–133 (2012).
- 13 Identification of a novel proteoform of prostate specific antigen (SNP-L132I) in clinical samples by multiple reaction monitoring. Mol. Cell Proteomics 12(10), 2761–2773 (2013).
- 14 Quantitative detection of single amino acid polymorphisms by targeted proteomics. J. Mol. Cell Biol. 3(5), 309–315 (2011).
- 15 . Analysis of intact protein isoforms by mass spectrometry. J. Biol. Chem. 286(29), 25451–25458 (2011).
- 16 . Mass spectrometric immunoassay revisited. J. Am. Soc. Mass Spectrom. 22(6), 960–968 (2011).
- 17 . Mass spectrometry-based protein assays for in vitro diagnostic testing. Expert Rev. Mol. Diagn. 12(3), 235–239 (2012).
- 18 . Quantitative mass spectrometry evaluation of human retinol binding protein 4 and related variants. PLoS ONE 6(3), e17282 (2011).
- 19 . Mass spectrometric immunoassay for quantitative determination of protein biomarker isoforms. J. Proteome Res. 9(11), 5969–5973 (2010).
- 20 . Mass spectrometric immunoassay for quantitative determination of transthyretin and its variants. Proteomics 11(18), 3633–3641 (2011).
- 21 . Targeted quantitative mass spectrometric immunoassay for human protein variants. Proteome Sci. 9(1), 19 (2011).
- 22 Parallel workflow for high-throughput (>1,000 samples/day) quantitative analysis of human insulin-like growth factor 1 using mass spectrometric immunoassay. PLoS ONE 9(3), e92801 (2014).
- 23 Mass spectrometric immunoassay for the qualitative and quantitative analysis of the cytokine macrophage migration inhibitory factor (MIF). Proteome Sci. 12(1), 52 (2014).
- 24 . Development of multiplex mass spectrometric immunoassay for detection and quantification of apolipoproteins C-I, C-II, C-III and their proteoforms. Methods 81, 86–92 (2015).
- 25 Detection of endogenous B-type natriuretic peptide at very low concentrations in patients with heart failure. Circ. Heart Fail. 1(4), 258–264 (2008).
- 26 Selected reaction monitoring-mass spectrometric immunoassay responsive to parathyroid hormone and related variants. Clin. Chem. 56(2), 281–290 (2010).
- 27 Multiple charged and aromatic residues in CCR5 amino-terminal domain are involved in high affinity binding of both chemokines and HIV-1 Env protein. J. Biol. Chem. 274(49), 34719–34727 (1999).
- 28 . Association of chemokine-mediated block to HIV entry with coreceptor internalization. J. Biol. Chem. 277(19), 17291–17299 (2002).
- 29 . Raised plasma concentration and ex vivo production of inflammatory chemokines in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 65(2), 209–215 (2006).
- 30 Suppressive effect of insulin infusion on chemokines and chemokine receptors. Diabetes Care 33(5), 1103–1108 (2010).
- 31 . RANTES (regulated on activation, normal T cell expressed and secreted), inflammation, obesity, and the metabolic syndrome. Circulation 115(8), 946–948 (2007).
- 32 . Plasma RANTES: a molecular fingerprint of the unstable carotid plaque? Eur. Heart J. 32(4), 393–395 (2011).
- 33 . Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ. Res. 100(1), 27–40 (2007).
- 34 . Platelet-derived chemokines in vascular remodeling and atherosclerosis. Semin. Thromb. Hemost. 36(2), 163–169 (2010).
- 35 . Chemokines in atherosclerosis, thrombosis, and vascular biology. Arterioscler. Thromb. Vasc. Biol. 28(11), 1896 (2008).
- 36 . Intrapersonal and populational heterogeneity of the chemokine RANTES. Clin. Chem. 56(9), 1432–1441 (2010).
- 37 . Multiple pathways of amino terminal processing produce two truncated variants of RANTES/CCL5. J. Leukoc. Biol. 78(2), 442–452 (2005).
- 38 . N-terminal proteolytic processing by cathepsin G converts RANTES/CCL5 and related analogs into a truncated 4–68 variant. J. Leukoc. Biol. 80(6), 1395–1404 (2006).
- 39 . Quantitative mass spectrometric immunoassay for the chemokine RANTES and its variants. J. Proteomics 116, 15–23 (2015).
- 40 Baseline levels and temporal stability of 27 multiplexed serum cytokine concentrations in healthy subjects. PLoS ONE 8(12), e76091 (2013).
- 41 Association of systemic chemokine concentrations with impaired glucose tolerance and Type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg Survey S4 (KORA S4). Diabetes 54(Suppl. 2), S11–S17 (2005).
- 42 . RBP4: a controversial adipokine. Eur. J. Endocrinol. 165(5), 703–711 (2011).
- 43 Serum levels of adipokine retinol-binding protein-4 in relation to renal function. Diabetes Care 30(10), 2588–2592 (2007).
- 44 Retinol binding protein 4 concentrations are influenced by renal function in patients with Type 2 diabetes mellitus. Metabolism 57(10), 1340–1344 (2008).
- 45 Serum retinol binding protein 4 contributes to insulin resistance in obesity and Type 2 diabetes. Nature 436(7049), 356–362 (2005).
- 46 Retinol-binding protein 4 as a plasma biomarker of renal dysfunction and cardiovascular disease in Type 2 diabetes. J. Intern. Med. 262(4), 496–503 (2007).
- 47 Increased levels of retinol binding protein 4 in patients with advanced heart failure correct after hemodynamic improvement through ventricular assist device placement. Circ. J. 76(9), 2148–2152 (2012).
- 48 . Characterization of two post-translationally processed forms of human serum retinol-binding protein: altered ratios in chronic renal failure. J. Lipid Res. 36(6), 1247–1253 (1995).
- 49 . Comparative phenotypic analyses of human plasma and urinary retinol binding protein using mass spectrometric immunoassay. Biochem. Biophys. Res. Commun. 297(2), 401–405 (2002).
- 50 . Investigating diversity in human plasma proteins. Proc. Natl Acad. Sci. USA 102(31), 10852–10857 (2005).
- 51 . Investigation of human protein variants and their frequency in the general population. Mol. Cell Proteomics 6(7), 1183–1187 (2007).
- 52 . Delineation of concentration ranges and longitudinal changes of human plasma protein variants. PLoS ONE 9(6), e100713 (2014).
- 53 Quantitative measurement of full-length and C-terminal proteolyzed RBP4 in serum of normal and insulin-resistant humans using a novel mass spectrometry immunoassay. Endocrinology 153(3), 1519–1527 (2012).
- 54 Plasma retinol-binding protein 4 (RBP4) levels and risk of coronary heart disease: a prospective analysis among women in the nurses’ health study. Circulation 127(19), 1938–1947 (2013).
- 55 . The structure of human retinol-binding protein (RBP) with its carrier protein transthyretin reveals an interaction with the carboxy terminus of RBP. Biochemistry 38(9), 2647–2653 (1999).
- 56 . Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler. Thromb. Vasc. Biol. 19(3), 472–484 (1999).
- 57 . Common genomic variation in the APOC3 promoter associated with variation in plasma lipoproteins. Arterioscler. Thromb. Vasc. Biol. 17(11), 2753–2758 (1997).
- 58 . Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371(1), 32–41 (2014).
- 59 Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 371(1), 22–31 (2014).
- 60 . Apolipoprotein C-III: going back to the future for a lipid drug target. Circ. Res. 112(11), 1405–1408 (2013).
- 61 Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ. Res. 112(11), 1479–1490 (2013).
- 62 . Mass spectral study of polymorphism of the apolipoproteins of very low density lipoprotein. J. Lipid Res. 40(3), 543–555 (1999).
- 63 . Mapping O-glycosylation of apolipoprotein C-III in MALDI-FT-ICR protein profiles. Proteomics 13(6), 992–1001 (2013).
- 64 . Mass spectrometry of apolipoprotein C-III, a simple analytical method for mucin-type O-glycosylation and its application to an autosomal recessive cutis laxa type-2 (ARCL2) patient. Glycobiology 22(8), 1140–1144 (2012).
- 65 . Relative quantitation of glycoisoforms of intact apolipoprotein C3 in human plasma by liquid chromatography-high-resolution mass spectrometry. Anal. Chem. 85(5), 2867–2874 (2013).
- 66 . Mass spectrometric identification of aberrantly glycosylated human apolipoprotein C-III peptides in urine from Schistosoma mansoni-infected individuals. Mol. Cell Proteomics 9(4), 667–681 (2010).
- 67 . Identification of new apolipoprotein-CIII glycoforms with ultrahigh resolution MALDI-FTICR mass spectrometry of human sera. J. Proteome Res. 12(5), 2260–2268 (2013).
- 68 The association of human apolipoprotein C-III sialylation proteoforms with plasma triglycerides. PLoS ONE 10(12), e0144138 (2015).
- 69 Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and Type 2 diabetes. J. Lipid Res. 57(5), 894–905 (2016).
- 70 . Serum amyloid A: the ‘other’ inflammatory protein. Curr. Atheroscler. Rep. 8(1), 62–68 (2006).
- 71 . Serum amyloid A, the major vertebrate acute-phase reactant. Eur. J. Biochem. 265(2), 501–523 (1999).
- 72 . Organization of the region encompassing the human serum amyloid A (SAA) gene family on chromosome 11p15.1. Genomics 23(2), 492–495 (1994).
- 73 . Revised nomenclature for serum amyloid A (SAA). Nomenclature Committee of the International Society of Amyloidosis. Part 2. Amyloid 6(1), 67–70 (1999).
- 74 . Characterization of human serum amyloid A protein isoforms separated by two-dimensional electrophoresis by liquid chromatography/electrospray ionization tandem mass spectrometry. Electrophoresis 17(5), 866–876 (1996).
- 75 Serum protein profiling by SELDI mass spectrometry: detection of multiple variants of serum amyloid alpha in renal cancer patients. Lab. Invest. 84(7), 845–856 (2004).
- 76 . Proteomics in molecular diagnosis: typing of amyloidosis. J. Biomed. Biotechnol. 754109 (2011).
- 77 . Detection of novel truncated forms of human serum amyloid A protein in human plasma. FEBS Lett. 537(1–3), 166–170 (2003).
- 78 Serum amyloid a truncations in Type 2 diabetes mellitus. PLoS ONE 10(1), e0115320 (2015).
- 79 . Identification of regions responsible for heparin-induced amyloidogenesis of human serum amyloid A using its fragment peptides. Arch. Biochem. Biophys. 511(1–2), 101–106 (2011).
- 80 . Rapid determination of transferrin isoforms by immunoaffinity liquid chromatography and electrospray mass spectrometry. Clin. Chem. 47(3), 513–518 (2001).
- 81 . Haemoglobin A1c: historical overview and current concepts. Diabetes Res. Clin. Pract. 99(2), 75–84 (2013).
- 82 . Applications of MALDI mass spectrometry in clinical chemistry. Clin. Chem. 62(1), 134–143 (2016).
- 83 . Recent development of mass spectrometry and proteomics applications in identification and typing of bacteria. Proteomics Clin. Appl. 10(4), 346–357 (2016).