Abstract
The discovery of the protein targets of small molecule probes is a crucial aspect of activity-based protein profiling and chemical biology. Mass spectrometry is the primary method for target identification, and in the last decade, cleavable linkers have become a popular strategy to facilitate protein enrichment and identification. In this chapter, we provide an overview of cleavable linkers used in chemical proteomics approaches, discuss their different chemistries, and describe how they aid in protein identification.
Key words
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Cox J, Mann M (2011) Quantitative, high-resolution proteomics for data-driven systems biology. Annu Rev Biochem 80:273–299. doi:10.1146/annurev-biochem-061308-093216
Rix U, Superti-Furga G (2009) Target profiling of small molecules by chemical proteomics. Nat Chem Biol 5(9):616–624. doi:10.1038/nchembio.216
Haedke U, Kuttler EV, Vosyka O, Yang Y, Verhelst SH (2013) Tuning probe selectivity for chemical proteomics applications. Curr Opin Chem Biol 17(1):102–109. doi:10.1016/j.cbpa.2012.11.024
Sadaghiani AM, Verhelst SH, Bogyo M (2007) Tagging and detection strategies for activity-based proteomics. Curr Opin Chem Biol 11(1):20–28. doi:10.1016/j.cbpa.2006.11.030
Willems LI, van der Linden WA, Li N, Li KY, Liu N, Hoogendoorn S, van der Marel GA, Florea BI, Overkleeft HS (2011) Bioorthogonal chemistry: applications in activity-based protein profiling. Acc Chem Res 44(9):718–729. doi:10.1021/ar200125k
Best MD (2009) Click chemistry and bioorthogonal reactions: unprecedented selectivity in the labeling of biological molecules. Biochemistry 48(28):6571–6584. doi:10.1021/bi9007726
Garret-Flaudy F, Freitag R (2000) Use of the avidin (imino)biotin system as a general approach to affinity precipitation. Biotechnol Bioeng 71(3):223–234
Flaster H, Kohn H (1981) Syntheses and spectral properties of 2-thiobiotin and biotin derivatives. J Heterocyclic Chem 18(7):1425–1436
Hirsch JD, Eslamizar L, Filanoski BJ, Malekzadeh N, Haugland RP, Beechem JM, Haugland RP (2002) Easily reversible desthiobiotin binding to streptavidin, avidin, and other biotin-binding proteins: uses for protein labeling, detection, and isolation. Anal Biochem 308(2):343–357
Ying LQ, Branchaud BP (2011) Design of a reversible biotin analog and applications in protein labeling, detection, and isolation. Chem Commun (Camb) 47(30):8593–8595. doi:10.1039/c1cc12738a
Leriche G, Chisholm L, Wagner A (2012) Cleavable linkers in chemical biology. Bioorg Med Chem 20(2):571–582. doi:10.1016/j.bmc.2011.07.048
van der Veken P, Dirksen EH, Ruijter E, Elgersma RC, Heck AJ, Rijkers DT, Slijper M, Liskamp RM (2005) Development of a novel chemical probe for the selective enrichment of phosphorylated serine- and threonine-containing peptides. Chembiochem 6(12):2271–2280. doi:10.1002/cbic.200500209
Fauq AH, Kache R, Khan MA, Vega IE (2006) Synthesis of acid-cleavable light isotope-coded affinity tags (ICAT-L) for potential use in proteomic expression profiling analysis. Bioconjug Chem 17(1):248–254. doi:10.1021/bc0503059
Truong TH, Garcia FJ, Seo YH, Carroll KS (2011) Isotope-coded chemical reporter and acid-cleavable affinity reagents for monitoring protein sulfenic acids. Bioorg Med Chem Lett 21(17):5015–5020. doi:10.1016/j.bmcl.2011.04.115
Szychowski J, Mahdavi A, Hodas JJ, Bagert JD, Ngo JT, Landgraf P, Dieterich DC, Schuman EM, Tirrell DA (2010) Cleavable biotin probes for labeling of biomolecules via azide-alkyne cycloaddition. J Am Chem Soc 132(51):18351–18360. doi:10.1021/ja1083909
Park KD, Liu R, Kohn H (2009) Useful tools for biomolecule isolation, detection, and identification: acylhydrazone-based cleavable linkers. Chem Biol 16(7):763–772. doi:10.1016/j.chembiol.2009.06.005
Dirksen A, Yegneswaran S, Dawson PE (2010) Bisaryl hydrazones as exchangeable biocompatible linkers. Angew Chem Int Ed Engl 49(11):2023–2027. doi:10.1002/anie.200906756
Claessen JH, Witte MD, Yoder NC, Zhu AY, Spooner E, Ploegh HL (2013) Catch-and-release probes applied to semi-intact cells reveal ubiquitin-specific protease expression in Chlamydia trachomatis infection. Chembiochem 14(3):343–352. doi:10.1002/cbic.201200701
Yang Y, Verhelst SH (2013) Cleavable trifunctional biotin reagents for protein labelling, capture and release. Chem Commun (Camb) 49(47):5366–5368. doi:10.1039/c3cc42076k
Jahng WJ, David C, Nesnas N, Nakanishi K, Rando RR (2003) A cleavable affinity biotinylating agent reveals a retinoid binding role for RPE65. Biochemistry 42(20):6159–6168. doi:10.1021/bi034002i
Lin D, Li J, Slebos RJ, Liebler DC (2010) Cysteinyl peptide capture for shotgun proteomics: global assessment of chemoselective fractionation. J Proteome Res 9(10):5461–5472. doi:10.1021/pr1007015
Sturm M, Leitner A, Lindner W (2011) Development of an indole-based chemically cleavable linker concept for immobilizing bait compounds for protein pull-down experiments. Bioconjug Chem 22(2):211–217. doi:10.1021/bc100330a
Geurink PP, Florea BI, Li N, Witte MD, Verasdonck J, Kuo CL, van der Marel GA, Overkleeft HS (2010) A cleavable linker based on the levulinoyl ester for activity-based protein profiling. Angew Chem Int Ed Engl 49(38):6802–6805. doi:10.1002/anie.201001767
Nielsen PE, Hansen JB, Buchardt O (1984) Photochemical cross-linking of protein and DNA in chromatin. Synthesis and application of a photosensitive cleavable derivative of 9-aminoacridine with two photoprobes connected through a disulphide-containing linker. Biochem J 223(2):519–526
Shimkus M, Levy J, Herman T (1985) A chemically cleavable biotinylated nucleotide: usefulness in the recovery of protein-DNA complexes from avidin affinity columns. Proc Natl Acad Sci U S A 82(9):2593–2597
Ichikawa M, Ichikawa Y (2001) A mechanism-based affinity-labeling agent for possible use in isolating N-acetylglucosaminidase. Bioorg Med Chem Lett 11(13):1769–1773
Gartner CA, Elias JE, Bakalarski CE, Gygi SP (2007) Catch-and-release reagents for broadscale quantitative proteomics analyses. J Proteome Res 6(4):1482–1491. doi:10.1021/pr060605f
Everley PA, Gartner CA, Haas W, Saghatelian A, Elias JE, Cravatt BF, Zetter BR, Gygi SP (2007) Assessing enzyme activities using stable isotope labeling and mass spectrometry. Mol Cell Proteomics 6(10):1771–1777. doi:10.1074/mcp.M700057-MCP200
Verhelst SH, Fonovic M, Bogyo M (2007) A mild chemically cleavable linker system for functional proteomic applications. Angew Chem Int Ed Engl 46(8):1284–1286. doi:10.1002/anie.200603811
Fonovic M, Verhelst SH, Sorum MT, Bogyo M (2007) Proteomics evaluation of chemically cleavable activity-based probes. Mol Cell Proteomics 6(10):1761–1770. doi:10.1074/mcp.M700124-MCP200
Leriche G, Budin G, Brino L, Wagner A (2010) Optimization of the azobenzene scaffold for reductive cleavage by dithionite; development of an azobenzene cleavable linker for proteomic applications. Eur J Org Chem 23:4360–4364. doi:10.1002/ejoc.201000546
Grammel M, Zhang MM, Hang HC (2010) Orthogonal alkynyl amino acid reporter for selective labeling of bacterial proteomes during infection. Angew Chem Int Ed Engl 49(34):5970–5974. doi:10.1002/anie.201002050
Landi F, Johansson CM, Campopiano DJ, Hulme AN (2010) Synthesis and application of a new cleavable linker for “click”-based affinity chromatography. Org Biomol Chem 8(1):56–59. doi:10.1039/b916693a
Yang YY, Grammel M, Raghavan AS, Charron G, Hang HC (2010) Comparative analysis of cleavable azobenzene-based affinity tags for bioorthogonal chemical proteomics. Chem Biol 17(11):1212–1222. doi:10.1016/j.chembiol.2010.09.012
Yang YY, Ascano JM, Hang HC (2010) Bioorthogonal chemical reporters for monitoring protein acetylation. J Am Chem Soc 132(11):3640–3641. doi:10.1021/ja908871t
Battenberg OA, Yang Y, Verhelst SH, Sieber SA (2013) Target profiling of 4-hydroxyderricin in S. aureus reveals seryl-tRNA synthetase binding and inhibition by covalent modification. Mol Biosyst 9(3):343–351. doi:10.1039/c2mb25446h
Qian Y, Martell J, Pace NJ, Ballard TE, Johnson DS, Weerapana E (2013) An isotopically tagged azobenzene-based cleavable linker for quantitative proteomics. Chembiochem 14(12):1410–1414. doi:10.1002/cbic.201300396
Yang Y, Hahne H, Kuster B, Verhelst SH (2013) A simple and effective cleavable linker for chemical proteomics applications. Mol Cell Proteomics 12(1):237–244. doi:10.1074/mcp.M112.021014
Maurer A, Zeyher C, Amin B, Kalbacher H (2013) A periodate-cleavable linker for functional proteomics under slightly acidic conditions: application for the analysis of intracellular aspartic proteases. J Proteome Res 12(1):199–207. doi:10.1021/pr300758c
Amore A, Wals K, Koekoek E, Hoppes R, Toebes M, Schumacher TN, Rodenko B, Ovaa H (2013) Development of a hypersensitive periodate-cleavable amino acid that is methionine- and disulfide-compatible and its application in MHC exchange reagents for T cell characterisation. Chembiochem 14(1):123–131. doi:10.1002/cbic.201200540
Wang PF (2013) Photolabile protecting groups: structure and reactivity. Asian J Org Chem 2(6):452–464. doi:10.1002/ajoc.201200197
Guillier F, Orain D, Bradley M (2000) Linkers and cleavage strategies in solid-phase organic synthesis and combinatorial chemistry. Chem Rev 100(6):2091–2157. doi:10.1021/cr980040+
Orth R, Sieber SA (2009) A photolabile linker for the mild and selective cleavage of enriched biomolecules from solid support. J Org Chem 74(21):8476–8479. doi:10.1021/jo901809k
Kim HY, Tallman KA, Liebler DC, Porter NA (2009) An azido-biotin reagent for use in the isolation of protein adducts of lipid-derived electrophiles by streptavidin catch and photorelease. Mol Cell Proteomics 8(9):2080–2089. doi:10.1074/mcp.M900121-MCP200
Carrington JC, Cary SM, Parks TD, Dougherty WG (1989) A second proteinase encoded by a plant potyvirus genome. EMBO J 8(2):365–370
Rigaut G, Shevchenko A, Rutz B, Wilm M, Mann M, Seraphin B (1999) A generic protein purification method for protein complex characterization and proteome exploration. Nat Biotechnol 17(10):1030–1032. doi:10.1038/13732
Puig O, Caspary F, Rigaut G, Rutz B, Bouveret E, Bragado-Nilsson E, Wilm M, Seraphin B (2001) The tandem affinity purification (TAP) method: a general procedure of protein complex purification. Methods 24(3):218–229. doi:10.1006/meth.2001.1183
Speers AE, Cravatt BF (2005) A tandem orthogonal proteolysis strategy for high-content chemical proteomics. J Am Chem Soc 127(28):10018–10019. doi:10.1021/ja0532842
Weerapana E, Speers AE, Cravatt BF (2007) Tandem orthogonal proteolysis-activity-based protein profiling (TOP-ABPP)–a general method for mapping sites of probe modification in proteomes. Nat Protoc 2(6):1414–1425. doi:10.1038/nprot.2007.194
Dieterich DC, Link AJ, Graumann J, Tirrell DA, Schuman EM (2006) Selective identification of newly synthesized proteins in mammalian cells using bioorthogonal noncanonical amino acid tagging (BONCAT). Proc Natl Acad Sci U S A 103(25):9482–9487. doi:10.1073/pnas.0601637103
Wright MH, Clough B, Rackham MD, Rangachari K, Brannigan JA, Grainger M, Moss DK, Bottrill AR, Heal WP, Broncel M, Serwa RA, Brady D, Mann DJ, Leatherbarrow RJ, Tewari R, Wilkinson AJ, Holder AA, Tate EW (2014) Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach. Nat Chem 6(2):112–121. doi:10.1038/Nchem.1830
Hashimoto M, Okamoto S, Nabeta K, Hatanaka Y (2004) Enzyme cleavable and biotinylated photoaffinity ligand with diazirine. Bioorg Med Chem Lett 14(10):2447–2450. doi:10.1016/j.bmcl.2004.03.011
Zheng TQ, Jiang H, Wu P (2013) Single-stranded DNA as a cleavable linker for bioorthogonal click chemistry-based proteomics. Bioconjug Chem 24(6):859–864. doi:10.1021/bc400093x
Park JJ, Sadakane Y, Masuda K, Tomohiro T, Nakano T, Hatanaka Y (2005) Synthesis of diazirinyl photoprobe carrying a novel cleavable biotin. Chembiochem 6(5):814–818. doi:10.1002/cbic.200400342
Kenner GW, Mcdermot JR, Sheppard RC (1971) Safety catch principle in solid phase peptide synthesis. J Chem Soc Chem Commun 12:636–637. doi:10.1039/c29710000636
Bongo NB, Tomohiro T, Hatanaka Y (2010) Efficient approach for profiling photoaffinity labeled peptides with a cleavable biotinyl photoprobe. Bioorg Med Chem Lett 20(6):1834–1836. doi:10.1016/j.bmcl.2010.01.164
Yokoshima S, Abe Y, Watanabe N, Kita Y, Kan T, Iwatsubo T, Tomita T, Fukuyama T (2009) Development of photoaffinity probes for gamma-secretase equipped with a nitrobenzenesulfonamide-type cleavable linker. Bioorg Med Chem Lett 19(24):6869–6871. doi:10.1016/j.bmcl.2009.10.086
Fukuyama T, Jow CK, Cheung M (1995) 2-Nitrobenzenesulfonamides and 4-nitrobenzenesulfonamides - exceptionally versatile means for preparation of secondary-amines and protection of amines. Tetrahedron Lett 36(36):6373–6374. doi:10.1016/0040-4039(95)01316-A
Milne SB, Tallman KA, Serwa R, Rouzer CA, Armstrong MD, Marnett LJ, Lukehart CM, Porter NA, Brown HA (2010) Capture and release of alkyne-derivatized glycerophospholipids using cobalt chemistry. Nat Chem Biol 6(3):205–207. doi:10.1038/Nchembio.311
Tallman KA, Armstrong MD, Milne SB, Marnett LJ, Brown HA, Porter NA (2013) Cobalt carbonyl complexes as probes for alkyne-tagged lipids. J Lipid Res 54(3):859–868. doi:10.1194/jlr.D033332
Egami H, Kamisuki S, Dodo K, Asanuma M, Hamashima Y, Sodeoka M (2011) Catch and release of alkyne-tagged molecules in water by a polymer-supported cobalt complex. Org Biomol Chem 9(22):7667–7670. doi:10.1039/c1ob06123b
Miyazaki A, Asanuma M, Dodo K, Egami H, Sodeoka M (2014) A “catch-and-release” protocol for alkyne-tagged molecules based on a resin-bound cobalt complex for peptide enrichment in aqueous media. Chem-Eur J 20(26):8116–8128. doi:10.1002/chem.201400056
Acknowledgements
We acknowledge funding by the Chinese Scholarship Council (to Y.Y.), the Slovenian Research Agency (ARRS grant to M.F.), the Deutsche Forschungsgemeinschaft (to S.V.) and the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein- Westfalen.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer Science+Business Media New York
About this protocol
Cite this protocol
Yang, Y., Fonović, M., Verhelst, S.H.L. (2017). Cleavable Linkers in Chemical Proteomics Applications. In: Overkleeft, H., Florea, B. (eds) Activity-Based Proteomics. Methods in Molecular Biology, vol 1491. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6439-0_14
Download citation
DOI: https://doi.org/10.1007/978-1-4939-6439-0_14
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-6437-6
Online ISBN: 978-1-4939-6439-0
eBook Packages: Springer Protocols