Abstract
Carbon dioxide is an omnipresent gas that drives adaptive responses within organisms from all domains of life. The molecular mechanisms by which proteins serve as sensors of CO2 are, accordingly, of great interest. Because CO2 is electrophilic, one way it can modulate protein biochemistry is by carboxylation of the amine group of lysine residues. However, the resulting CO2-carboxylated lysines spontaneously decompose, giving off CO2, which makes studying this modification difficult. Here we describe a method to stably mimic CO2-carboxylated lysine residues in proteins. We leverage this method to develop a quantitative approach to identify CO2-carboxylated lysines of proteins and explore the lysine ‘carboxylome’ of the CO2-responsive cyanobacterium Synechocystis sp. We uncover one CO2-carboxylated lysine within the effector binding pocket of the metabolic signaling protein PII. CO2-carboxylatation of this lysine markedly lowers the affinity of PII for its regulatory effector ligand ATP, illuminating a negative molecular control mechanism mediated by CO2.
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Data availability
All raw proteomics data were deposited to the ProteomeXchange Consortium via the PRIDE partner repository, with the dataset identifier (PXD031976). The hCit OXA-48 crystal structure has been deposited in the PDB with accession code 7LXG. The PDB codes for previously determined X-ray crystallographic structures used in the preparation of this manuscript are as follows: OXA-48 (4S2P), apo Synechocystis sp. PII (1UL3), ATP/2-OG bound S. elongatus PII (2XUL) and A. thaliana PII (2O66). The NCBI accession codes used in generating recombinant proteins for this study are as follows: K. pneumoniae OXA-48 (API82700), Synechocystis sp. PII (CAA66127.1) and A. thaliana PII (OAP00825.1). UniProt reference proteomes used in LysCarComp–MS analysis are as follows: E. coli K12 (UP000000625), Synechocystis sp. 6803 (UP000001425) and K. pneumoniae OXA-48 (Q6XEC0). All other data needed to evaluate the conclusions in the manuscript are available within the main text or supplementary materials. Source data are provided with this paper.
Code availability
No custom code was generated.
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Acknowledgements
We are grateful to the Natural Sciences and Engineering Research Council of Canada (NSERC) (grant no. RGPIN298406) and the Human Frontiers Science Program (grant no. RGP0058/2020) for supporting this research. D.J.V. thanks the Canada Research Chairs program for support as a Tier I Canada Research Chair in Chemical Biology. D.T.K. is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (CIHR) and a Trainee Award from the Michael Smith Foundation for Health Research and Pacific Alzheimer Research Foundation. We acknowledge the UVic-Genome BC Proteomics Centre, Victoria, Canada for performing all MS experiments. X-ray crystallography was performed at the Canadian Light Source synchrotron facility, a national research facility of the University of Saskatchewan, which is supported by the Canada Foundation for Innovation (CFI), NSERC, the National Research Council (NRC), CIHR, the Government of Saskatchewan and the University of Saskatchewan. We are grateful to L. Craig, S. Cecioni, Y. Zhu and M. Alteen for their expert input. Parts of the schematics were generated using BioRender.com.
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Contributions
D.J.V. and D.T.K. conceived and designed experiments. D.T.K., Z.M. and S.K. performed plasmid construction and protein purification. D.T.K. performed biochemistry experiments, MS preparations and data analysis. D.T.K and J.E.S.N. performed X-ray crystallography and data analysis, D.B.H. performed MS, and D.T.K. and D.B.H. analyzed the MS data. S.Z. performed the NMR experiments and analyzed the data. D.J.V. and D.T.K. analyzed other data and wrote the manuscript with input from all.
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Nature Chemical Biology thanks Cong-Zhao Zhou and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Extended data
Extended Data Fig. 1 Homocitrullination of OXA-48 Lys73 blocks catalytic activity.
a-b, Mechanistic diagram of WT (Lys73-CO2) and homocitrullinated (hCit73) OXA-48 showing how hCit73 is unable to act as a general base and activate the nucleophilic serine.
Extended Data Fig. 2 In vitro OCNH-mediated homocitrullination of OXA-48, related to Fig. 1.
a, IC50 experiments comparing OXA-48 inhibition by CO2 analogues. Data represent mean values ± SD from n = 4 independent experiments. b, Far-UV CD spectra of OXA-48 pre-incubated in the presence of 50 mM NaCl or 50 mM KOCN. Data represent mean values ± SD from n = 4 independent experiments. c, Activity assays on samples from (b) taken immediately before (0 hrs) and after CD (6 hrs). OXA-48 remains inactivated throughout the CD experiment. Data represent means ± SD from n = 3 independent experiments. d, Jump-dilution kinetics experiments to detect time-dependant decarbamylation of OXA-48. Data represent mean values ± SD from n = 6 independent experiments. e, Anti-His immunoblot for OXA-48 samples from (d) incubated in the presence of either 50 mM NaCl or 50 mM KOCN at 0- and 48-hour timepoints. Samples were centrifuged to remove insoluble aggregates prior to immunoblotting. This immunoblot was performed once. f, Immunoblot competition assays for WT and K73A OXA-48. The image shown in f is a representative image from three independent experiments. g, Densitometry analysis of select bands from (f). The chart displays mean ± SD from two experimental replicates with P values: two tailed student’s t-test assuming unequal variance; **P < 0.01. The indicated significant P values in (g) are as follows: (50 mM KOCN) vs. (50 mM KOCN, 50 mM NaHCO3) = 0.00346, (50 mM KOCN, 50 mM NaHCO3) vs. (50 mM KOCN, 50 mM NaCl) = 0.00337. h, Crystallographic evidence for hCit73 OXA-48. The hCit73 omit Fo-Fc electron density map contoured at 3.5 σ is shown overlaid on the final refined coordinates. The protein backbone is displayed in magenta cartoon with key active site residues displayed as white sticks with heteroatoms coloured by type. The hCit73 residue is displayed as green sticks. Select hydrogen bonds are shown as blue dashes.
Extended Data Fig. 3 CO2 competes with OCNH on OXA-48 in a concentration dependant manner, related to Fig. 2.
a, Immunoblot competition assay performed on purified OXA-48 with detection using a polyclonal anti-hCit antibody. b, Densitometry analysis of relative OXA-48 band intensities in a. Data points are normalized to the Anti-His control band and then again to the zero NaHCO3 control. Data are fit to a three-parameter sigmoidal dose-response curve in GraphPad Prism.
Extended Data Fig. 4 Lys-CO2 modification of RuBisCO large subunit identified by proteome wide LysCarComp-MS performed on Synechocystis sp., related to Fig. 4.
a, LC-MS/MS spectra showing unambiguous evidence for hCit196 residue within TMTduplex-labelled RuBisCO large subunit peptide [TMT-GGLDFThCit(K196 + 43.01 Da)DDENINSQPFMR, MH + [Da] = 2452.16]. b, Close-up of TMTduplex reporter ions and immonium ions derived from (a). The mean RCO2 with SD from three independent experimental replicates is given.
Extended Data Fig. 6 CO2 blocks BODIPY FL ATP-γ-S binding to PII from Synechocystis sp., related to Fig. 5.
a, FP equilibrium dissociation binding of BODIPY FL ATP-γ-S to WT and K90A SsPII. b-c, FP equilibrium competition binding experiments for WT (b) and K90A SsPII (c) in the presence of varying concentrations of small molecules (2-OG, GTP, UDP, ADP, ATP). d, Time-dependant effect of KOCN on FP equilibrium probe binding to WT and K90A SsPII. e, FP equilibrium binding of BODIPY FL ATP-γ-S following pre-incubation of SsPII in the presence and absence of KOCN followed by jump dilution and desalting to remove residual KOCN. In (a-e), all data is presented as mean values ± SD from n = 2 independent experiments. f, FP equilibrium competition binding experiments for WT and K90A SsPII in the presence of varying concentrations of HCO3−. Data in (f) are presented as mean values ± SD from n = 4 independent experiments. In (b) and (f), KD’s for competitor compounds were calculated from IC50 values using a standard FP equilibrium binding formula as previously described59. KD(CO2) was determined from KD using standard equations for carbonate equilibria as previously described60.
Extended Data Fig. 7 Biolayer interferometry confirms that CO2 blocks ATP binding to SsPII, related to Fig. 5.
a, Chemical structure of the biotin-conjugated ATP analogue used in BLI. b-c, Representative independent duplicate BLI association/dissociation curves for WT SsPII run in the absence (b) and presence (c) of 50 mM HCO3−. d, Representative BLI association/dissociation curves for K90A SsPII run in the absence of HCO3−. SsPII protein concentrations and curves are exactly as shown in b-c. e, Equilibrium response ratio for SsPII binding to the ATP-biotin probe in the presence and absence of 50 mM HCO3−. Req values correspond to the response value at the 240 s timepoint in b and c. Data are presented as mean values ± SD from three independent experiments.
Extended Data Fig. 8 Lys164-CO2 modification blocks ATP binding to PII from Arabidopsis thaliana.
a, Active site overlay of apo SsPII and apo Arabidopsis thaliana PII (AtPII, 53.6% sequence identity, PDB IDs: 1UL3 and 2O66). The SsPII and AtPII protein chains are displayed as green and yellow cartoons with select residues shown as sticks with atoms coloured by type. b, 13C NMR using purified WT and K164A AtPII in the presence and absence of 50 mM NaH13CO3. c, FP equilibrium dissociation binding of BODIPY FL ATP-γ-S to WT and K164A AtPII. d, FP equilibrium competition binding experiments for WT and K164A AtPII in the presence of varying concentrations of HCO3−. In c-d, data are presented as mean values ± SD from n = 2 independent experiments. In d, KD’s for competitor compounds were calculated from IC50 values using a standard FP equilibrium binding formula as previously described59. KD(CO2) was determined from KD using standard equations for carbonate equilibria as previously described60.
Supplementary information
Supplementary Information
Supplementary Figs. 1–9, Tables 1–5 and Uncropped gel images.
Supplementary Data 1
Excel-based data table summarizing all LysCarComp–MS proteomics data. The table includes the amino acid sequence, accession numbers, modification site(s), missed cleavages, PSMs, confidence scores (XCorr) and relative reporter ion intensities across all replicates for every peptide identified.
Supplementary Data 2
Excel-based data table with source data for Supplementary Fig. 2. Includes an LC–MS/MS analysis of various OCNH adducts on tryptic peptides derived from OXA-48.
Supplementary Data 3
Excel-based data table with source data for Supplementary Fig. 5. Includes a kinetic analysis of OXA-48 activity following addition of various amounts of N3-PEG4-NCO.
Supplementary Data 4
Excel-based data table with source data for Supplementary Fig. 6. Includes a kinetic analysis of OXA-48 activity determined at different pH values.
Supplementary Data 5
Excel-based data table with source data for Supplementary Fig. 7. Includes data for aggregation assays performed using cellular lysates in the presence and absence of both OCNH and HCO3−. Also, the table includes a kinetic analysis of OXA-48 activity determined in the presence and absence of supplementary carbonic anhydrase.
Supplementary Data 6
Excel-based data table with source data for Supplementary Fig. 8. Includes LC–MS/MS data used in mapping the synthetic hCit OXA-48 peptide.
Source data
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Source data for Extended Data Fig. 8b–d.
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King, D.T., Zhu, S., Hardie, D.B. et al. Chemoproteomic identification of CO2-dependent lysine carboxylation in proteins. Nat Chem Biol 18, 782–791 (2022). https://doi.org/10.1038/s41589-022-01043-1
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DOI: https://doi.org/10.1038/s41589-022-01043-1
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