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Letter
Establishing Signature Fragments for Identification and Sequencing of Dityrosine Cross-linked Peptides using Ultraviolet Photodissociation Mass Spectrometry Soumya Mukherjee, Mengxuan Fang, Woan Mei Kok, Eugene A. Kapp, Varsha J. Thombare, Romain Huguet, Craig A Hutton, Gavin E. Reid, and Blaine R. Roberts Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b02986 • Publication Date (Web): 06 Sep 2019 Downloaded from pubs.acs.org on September 6, 2019
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Analytical Chemistry
Establishing Signature Fragments for Identification and Sequencing of Dityrosine Cross-linked Peptides using Ultraviolet Photodissociation Mass Spectrometry Soumya Mukherjee,1 Mengxuan Fang,2 W. Mei Kok,3 Eugene A. Kapp,1 Varsha J. Thombare,2 Romain Huguet,4 Craig A. Hutton,2 Gavin E. Reid,*2,5 Blaine R. Roberts*1 1Florey
Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, 3010, Australia of Chemistry, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, 3010, Australia 3University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland, 4072, Australia 2School
4Thermo
Fisher Scientific, San Jose, California, 95134, U.S.A. of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, 3010, Australia
5Department
ABSTRACT: Dityrosine cross-linking of A peptides and -synuclein is increasingly becoming recognized as a biomarker of neuropathological diseases. However, there remains a need for the development of analytical methods that enable the specific and selective identification of dityrosine cross-linked proteins and peptides in complex biological samples. Here, we report that the gasphase fragmentation of protonated dityrosine cross-linked peptides under ultraviolet photodissociation (UVPD) tandem mass spectrometry (MS/MS) conditions results in the cleavage across C and C atoms of the dityrosine residue. This CC cleavage in UVPD–MS/MS results in the formation of diagnostic pairs of product ions, providing information of the two individual peptides involved in the cross-linking—resolving the intrinsic “n2 problem” plaguing the identification of this post-translational modification (PTM) by tandem mass spectrometry. Sequencing of a heterodimeric dityrosine cross-linked peptide was demonstrated using hybrid UVPD-MS/MS and CID–MS3 on a diagnostic pair of product ions. In combination with dedicated MS–cleavable MSn software, UVPD–MSn therefore provides an avenue to selectively discover and describe dityrosine cross-linked peptides. Additionally, observation of dityrosine-specific “reporter ions” at m/z 240.1019 and m/z 223.0752 in UVPD-MS/MS will be useful for the validation of the dityrosine cross-linked peptides.
Advances in mass spectrometric techniques in analyzing covalent PTMs of proteins such as phosphorylation, ubiquitination, acetylation, lipidation and glycosylation have proven useful in providing invaluable insights into the fundamental cellular regulatory mechanisms involved in the development of diseases.1 Oxidative stress and nitrative stress from reactive oxygen/nitrogen species (ROS/RNS) can alter protein structure and function.2 Covalent cross-linking of tyrosine to form dityrosine is a common biomarker of oxidative stress, aging and diverse pathological conditions such as in Alzheimer’s Disease (AD) and Parkinson’s Disease (PD).3 Dityrosine cross-linked A peptides and -synuclein have been reported in AD brain4 and PD brain,5 respectively, and have been demonstrated as the minimal toxic oligomeric species in vitro.6 Unlike other common PTMs, routine identification of dityrosine in proteins by mass spectrometry cannot be achieved by traditional database search.7 A workflow was recently described for characterization and identification of in vitro dityrosine cross-linked peptides in a bottom-up proteomic approach, using both collisional activation (e.g., CID and HCD) and electron-based (e.g., ETD and ECD) tandem mass spectrometry dissociation (MS/MS) methods for ion activation.7 However, the absence of any diagnostic fragment ions using these common fragmentation
methods demands a priori knowledge of all the possible peptide candidates in order to probe for the dityrosine cross-linked peptides using standard database search methods.7-8 This is because data complexity increases as a square of the number of potential peptide candidates (referred to as “n2 problem”) in the database.9 Furthermore, imperfect/unequal fragmentation efficiency of the two cross-linked peptides in MS/MS10 impairs confident assignment and identification of the cross-linked peptides due to high false discovery rates (FDR).11 This limits the application of conventional MS/MS techniques on a global proteomic scale, thereby impeding the process of discovery of dityrosine cross-linked proteins and peptides in biologically complex samples. Specific identification of this PTM could potentially provide endogenous protein interaction information under pathological conditions. To date, analytical methods for purifying and identifying dityrosine molecule have universally depended on its unique characteristic fluorescence (exci ~ 280 nm and em ~ 420 nm).7,12 Here, we investigated if any mass spectrometric technique could access this electronic excitation of the dityrosine chromophore for specific fragmentation, as has been done for other cross-linked peptides by introducing MScleavable moieties for generation of signature fragment ion pairs.13 Utilization of the signature fragment ion pairs upon MSn
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Figure 2. Schematic representation of the Cα–Cβ bond cleavage in protonated dityrosine peptide upon electronic excitation in UVPD– MS/MS.
Figure 1. (A) HCD and (B) 213 nm UVPD–MS/MS spectra of the source cleaved singly charged (m/z 361.1387) precursor ion of dityrosine molecule with 25 ms laser irradiation.
allows software algorithms to specifically identify the crosslinked peptides from database searching.14 Ultraviolet photodissociation (UVPD) tandem mass spectrometry (MS/MS) has emerged as an alternative fragmentation technique for proteomics and lipidomics,15 where ions dissociate following the absorption of one or more UV photons (e.g., 6.4 eV at 193 nm).16 UVPD of protonated or deprotonated peptide ions involves electronic excitation of the peptide amide group17 and provides fragmentation pathways different from collisional-15a,18 or electron-based dissociation processes.19 This leads to comprehensive sequence coverage through the production of a, b, c, x, y and z ions.15a,20 Recently, 193 nm UVPD–MS/MS has been used for both top-down21 and bottom-up proteomics,22 as well as phosphoproteomic analysis.23 Peptides with aromatic residues (i.e. tyrosine, tryptophan, phenylalanine) undergo UV laser-induced – transition, thereby leading to specific CC cleavage of the aromatic residues.24 To establish the specific fragmentation behaviour of dityrosine cross-linked peptides in UVPD–MS/MS, we first compared the fragmentation of protonated dityrosine under HCD (Figure 1A) versus 213 nm UVPD–MS/MS conditions (Figure 1B) as well as 193 nm UVPD–MS/MS conditions (Figure S1). 213 nm UVPD–MS/MS of the protonated dityrosine m/z 361.1393 precursor ion resulted in a series of neutral loss products, the same as those observed by HCD– MS/MS (Figure 1A). However, unique product ions were also observed at m/z 287.1149 (C16H17O4N1), m/z 286.1071 (C16H16O4N1) in the UVPD–MS/MS spectrum, due to characteristic CC peptide-dityrosine bond cleavage (Figure 1B and S1) along with the dityrosine specific reporter ions at m/z 240.1016 (C15H14O2N1) and 223.0752 (C15H11O2). The
overall fragmentation efficiency by HCD was ~ 44 %, while UVPD had ~ 68-80 % efficiency (Table S1). A homolytic CC bond cleavage due to – excitation leads to the formation of m/z 287.1149 ion (Figure 2). H-atom loss after intramolecular vibrational redistribution from the m/z 287.1149 ion would form the semi-quinone fragment ion m/z 286.1071 (Figure 2), subsequently forming the diagnostic m/z 240.1016 (dityrosine immonium ion) and m/z 223.0752 ions. The fragment ions lower than m/z 223.0752 observed in UVPD– MS/MS of protonated dityrosine (i.e. m/z 207.0805, m/z 189.0699, m/z 165.0699) are not observed in more complex peptide systems (vide infra). Next a synthetic dityrosine cross-linked [GYAK]2 homodimer peptide was used as a model system to study the UVPD–MS/MS fragmentation behaviour in a more complex species other than dityrosine (dipeptide). 213 nm UVPD– MS/MS (Figure 3) of the [M+2H]2+ m/z 437.2196 precursor ion resulted in complete amino acid sequence coverage via the observation of an, bn, yn, cn and zn ions (Figure 3). These fragments were also observed by HCD fragmentation (Figure S2). However, unique ions that distinguished the 213 nm UVPD–MS/MS (Figure 3) or 193 nm UVPD–MS/MS (Figure S3) from HCD–MS/MS (Figure S2) included Cα–Cβ cleavage peptide fragment ion pairs at m/z 543.2680 (C27H37O7N5) and m/z 331.1846 (C13H25O5N5) (Figure 3). Most importantly, dityrosine specific “reporter” ions m/z 240.1018 and m/z 223.0754 were also observed in the UVPD–MS/MS (Figure 3 and S3). Homolytic Cα–Cβ peptide-dityrosine bond cleavage due to – excitation would lead to the formation of peptide fragment ion pairs m/z 543.2680 (α’ peptide) / m/z 331.1846 (’ peptide) (Figure 3). H-atom loss from the dityrosine radical cation m/z 543.2680 (Figure S4) forms the semi-quinone ion m/z 542.2603 (Figure S4), that subsequently decays to form the dityrosine specific “reporter” ions m/z 240.1018 (dityrosine immonium ion) and m/z 223.0754 similar to the protonated dityrosine (Figure 2). Recently, a dityrosine cross-linked [A(6–16)]2 peptide has been reported by immunoprecipitation (IP)–MS/MS from AD
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Analytical Chemistry multiply charged cross-linked peptides. 213 nm UVPD-MS/MS spectrum of the precursor [M+5H]5+ (m/z 782.1512) ion of the dityrosine cross-linked [A(1–16)]2 homodimer displayed an array of a, b, c, y and z ions as expected (Figure S5). Registration of N-terminal ions, C-terminal ions along with the multiply charged bn, yn, xn, cn and zn (Figure S5) ions led to complete sequence coverage. Importantly, Cα–Cβ cleavage led to the formation of multiply charged diagnostic peptide fragment ion pairs — α’ peptide with the dityrosine chromophore attached ([M+3H]3+ m/z 687.3073 and [M+2H]2+ m/z 1030.4573), and their counterpart ’ peptide without the dityrosine chromophore ([M+2H]2+ m/z 924.4174 and [M+3H]3+ m/z 616.6141) (Figure S5). The dityrosine specific reporter (dityrosine immonium ion) m/z 240.1019 ion (Figure S5, inset) was also observed via 213 nm UVPD-MS/MS of this [A(1–16)]2 homodimer.
Figure 3. The 213 nm UVPD–MS/MS of the dityrosine crosslinked [GYAK]2 homodimer peptide [M+2H]2+ m/z 437.2264 ion irradiated for 50 ms. The semi-quinone fragment ion m/z 542.2603 and Cα–Cβ fragment ion pairs m/z 543.2680 and m/z 331.1846 are shown in red. Dityrosine specific reporter ions m/z 240.1019 (dityrosine immonium ion) and m/z 223.0754 is indicated in blue.
brain, implicating the potential of dityrosine cross-linked peptides to serve as clinical biomarkers of oxidative stress in neurodegenerative diseases.4 Thus, as a proof-of-principle demonstration, we investigated the 213 nm UVPD–MS/MS of both the dityrosine cross-linked [A(1-16)]2 homodimeric as well as a [A(1–16)–A(1–10)] heterodimeric peptide to understand the photoionization efficiency of the peptide fragment pairs and dityrosine specific “reporter” ions in these
213 nm UVPD-MS/MS of the dityrosine cross-linked [A(1– 16)–A(1–10)] heterodimer was more interesting as it had an additional C-terminus N-ethyl amide modification in the peptide sequence (Figure 4). The complete identity of the plaque derived neurotoxic ~7 kDa A species is still elusive due to its heterogeneity and could be possibly have dityrosine crosslinked heterodimer, with additional PTMs.25 213 nm UVPDMS/MS of the [M+5H]5+ m/z 635.8852 precursor (Figure 4A) led to the formation of the expected peptide fragment ion pairs — an α’ [A(1–16)] peptide with the dityrosine chromophore [M+3H]3+ m/z 687.3073 and the corresponding ’ [A(1–10)] peptide without the dityrosine chromophore [M+2H]2+ m/z 558.7505. Similarly, the complementary Cα–Cβ fragment pair — an α” [A(1–16)] peptide without the dityrosine chromophore [M+3H]3+ m/z 616.6136 and the corresponding ” [A(1–10)] peptide with the dityrosine chromophore [M+2H]2+
Figure 4. (A) 213 nm UVPD–MS/MS of the [M+5H]5+ m/z 635.8848 precursor ion of the dityrosine cross-linked [A(1–16)–A(1–10)] heterodimer, laser irradiation time 35 ms. The two set of peptide fragment ion pairs ’ [M+3H]3+ m/z 687.3073 / ’ [M+2H]2+ m/z 558.7505 and " [M+3H]3+ m/z 616.6143 / " [M+2H]2+ m/z 664.2885 are indicated by red. The inset shows the dityrosine immonium “reporter” ion m/z 240.1019 in blue. (B) MS3-UVPD-CID spectra of the ’–peptide [M+3H]3+ m/z 687.3071 fragment ion with the dityrosine chromophore attached, while (C) MS3-UVPD-CID spectra of the ’–peptide of the heterodimer [M+2H]2+ m/z 558.7505 fragment ion with N-ethyl amide C-terminus modification. The * indicates Arginine side chain loss.
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m/z 664.2876 were also observed (Figure 4A). MS3-UVPD– CID fragmentation of the α’/’ ion pair was then performed to verify the sequence of the two individual peptides involved in this heterodimeric dityrosine cross-link. Observation of b112+, b122+, b132+, b133+, b142+, b152+ and y9+, y153+ ions from CID–MS3 of the [M+3H]3+ m/z 687.3073 ion (α’ peptide) ion confirmed this unique fragment ion indeed had the dityrosine chromophore attached to A(1–16) (Figure 4B), while b3+, a6+, a62+, a72+, c72+ and a102+, along with C-terminal ions y8+, y82+, y92+ and z6+ ions from CID-MS3 of the [M+2H]2+ m/z 558.75 ion confirmed that the ’ peptide was A(1–10) with an N-ethyl amide modified C-terminus (Figure 4C). The sequencing of the individual peptides involved in this dityrosine cross-linked heterodimer using UVPD-MS/MS and CID-MS3 is a significant analytical improvement that enables reduction of the “n2 problem” to a search space of just the total number of possible candidate peptides in the database. This makes de novo sequencing a possibility for dityrosine cross-linked proteins and peptides with more than one tyrosine residue in the individual peptide sequence. Furthermore, the hybrid UVPD–MSn of peptide fragment pairs also reconciles the issue of unequal/inefficient fragmentation efficiency that has plagued cross-linked peptide research. Most importantly, the observation of dityrosine specific “reporter ion” at low m/z (Figure 3, 4A and S5) in the UVPD-MS/MS also helps in the authentication of the presence of the dityrosine residue in the cross-linked peptides, similar to protein interaction reporter (PIR) method.26 At present only a few MSn software tools e.g. XlinkX and MeroX, provide capability to analyze MS-cleavable crosslinking data.13a,14a,c While XlinkX retrieves the precursor mass of each linked peptide on the basis of a unique mass difference (the Δm principle) derived from the gas-phase dissociation of the cross-linker, MeroX uses the signature fragment ions from MS-cleavable cross-linkers to increase confidence in cross-link identification. As a proof-of-concept the UVPD-MS/MS spectrum from the [M+5H]5+ precursor ions of both the dityrosine cross-linked [A(1–16)]2 homodimer as well as [A(1–16) –A(1–10)] heterodimer were searched using MeroX against an in-house A database (Table S2). MeroX was able to identify both the dityrosine cross-linked A peptides (Figure S6 and S7), as predicted, due to the accurate assignment of both signature peptide fragment ion pairs as well as the dityrosine immonium ion at m/z 240.1018 in these spectra. This specificity of validating the dityrosine cross-linked peptides in the UVPD–MS/MS from “reporter ion” observation will depend on the potential level of isobaric interference to the m/z 240.1018 ion from other dipeptide fragment ions as well as the intensity of this ions in the spectra, which has to be experimentally determined. In conclusion, our findings indicate that UVPD–MSn can be used for the identification and sequencing of protonated dityrosine cross-linked peptides. The Cα–Cβ fragmentation leads to signature fragment ion pairs which allows this PTM to be treated like any MS-cleavable cross-link. Thus, in combination with dedicated MS-cleavable MSn software, UVPD–MSn provides an avenue to sequence dityrosine cross-linked peptides. Finally, UVPD of dityrosine cross-linked peptides has the potential to provide novel insights to this elusive modification as well as the proteins involved in the cross-linking.
ASSOCIATED CONTENT Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: xxx/xxx. Experimental, 193 nm UVPD–MS/MS of protonated dityrosine, fragmentation efficiencies of common and diagnostic ions in HCD vs 193/213 nm UVPD for protonated dityrosine (Table S1), HCD and 193 nm UVPD–MS/MS of dityrosine cross-linked [GYAK]2 homodimer, scheme for Cα–Cβ bond cleavage of dityrosine cross-linked [GYAK]2 homodimer, 213 nm UVPD-MS/MS of dityrosine crosslinked [A(1–16)]2 homodimer, annotated UVPD–MS/MS spectra searched with MeroX software for dityrosine cross-linked [A(1– 16)]2 homodimer and [A(1–16)–A(1–10)] heterodimer (PDF). The A.txt file (Table S2).
AUTHOR INFORMATION Corresponding Author *
[email protected] *
[email protected] Notes G.E.R receives research support from Thermo Fisher Scientific. R.H. is an employee of Thermo Fisher Scientific. All other authors declare no competing financial interests.
ACKNOWLEDGMENT The authors acknowledge funding from the Victorian Government’s Operational Infrastructure Support program, the National Health and Medical Research Council Grant APP1138673, APP1164692 (B.R.R.), Alzheimer’s Disease Drug Discovery Foundation (ADDF) (B.R.R.) and the Australian Research Council LE160100015 (G.E.R), DP190102464 (G.E.R.), DP120101454 (C.A.H.) and DP140100174 (C.A.H.).
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