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A Click‐Chemistry‐Based Enrichable Crosslinker for Structural And DOI:10.1002/cbic.201900611 Communications AClick-Chemistry-Based Enrichable Crosslinker for Structural and Protein Interaction Analysis by Mass Spectrometry Michael Stadlmeier+,[a, b] Leander SimonRuntsch+,[a] Filipp Streshnev,[a] MartinWühr,[b] and Thomas Carell*[a] Mass spectrometry is the method of choice for the characteri- and demethylation.[3–5] This showcasesthe need to study the sation of proteomes. Most proteins operate in protein com- complex environment of agiven protein to analyse its function plexes, in which their close associationmodulates their func- and activity state. Protein crosslinking, in combination with tion. However,with standard MS analysis, information on pro- analysisbymass spectrometry (XL-MS), is ideally suited as a tein–protein interactions is lost and no structural information is methodtogain information about protein structure and the retained. To gain structuraland interactome data, new cross- composition of protein complexes.[6–9] For XL-MS, specialised linking reagents are neededthat freeze inter- and intramolecu- chemicalreagents, crosslinkers, are required, which are able to lar interactions. Herein, the development of anew reagent, covalently connect protein residues that are in close proximity, which has severalfeaturesthat enable highly sensitive cross- for example, interacting in acomplex.[10,11] Characterisation of linking MS, is reported.The reagent enables enrichmentof the crosslinked peptides by meansofmass spectrometry,how- crosslinked peptides from the majority of background peptides ever,poses aformidable challenge for two reasons. Firstly, to facilitate efficient detection of low-abundant crosslinked crosslink identification has to be achieved by analysing frag- peptides. Due to the special cleavable properties, the reagent ment ions of not only one, buttwo, connected peptides, can be used for MS2 and potentially for MS3 experiments. Thus, thereby massively complicating MS2 spectra. Secondly,the the new crosslinking reagent, in combination with high-end crosslinked peptidespecies have only avery low abundance MS, should enable sensitive analysis of interactomes, which and are part of apeptide mixture that is overwhelmingly do- will help researchers to obtainimportant insights into cellular minatedbynon-crosslinked peptides. In many cases, this leads states in health and diseases. to dramatic information loss that hampers accurate crosslink identification, and therefore, interactome analysis. Afew cross- linking reagents were developed, which introduced MS-cleav- Proteinsneed to interactwith other proteins to form function- able groups, and the possibility for XL enrichmenttotackle al complexes. In many cases, protein function inside cells these problems.[12–18] cannotbeunderstood without information about the protein Herein, we report the development of anew crosslinking re- structure and knowledge of in whichcomplex the protein is agent that is enrichable and has cleavage properties which situated.[1,2] Thisis, for example, of paramount importance for allow accuratecrosslink identification. The designed cliXlink (1) proteins that modulate epigenetic informationonDNA. Almost is depicted in Figure 1. The cell-permeable reagent (Figure 1A all of these chromatin-modifying proteins require intensivein- and Figure S1 in the Supporting Information) features two suc- teraction with metabolic enzymes,which provide the cofactors cinimidyl ester units that can react with nucleophilesinpro- neededfor histone acetylation, deacetylation or methylation teins and are spacedroughly 9 apart;thus enabling the fixa- tion of short distances to gain structuralinformation on pro- + + [a] Dr.M.Stadlmeier, L. S. Runtsch, F. Streshnev,Prof. Dr.T.Carell teins and to capture proteins in close proximity to each other. Department of Chemistry,Ludwig-Maximilians-UniversitätMünchen Butenandtstrasse5–13,81377Munich(Germany) Efficient MS cleavability is ensured by the well-established sulf- E-mail:[email protected] oxide group, which can be cleaved under low-energy collision- [b] Dr.M.Stadlmeier,+ Prof. Dr.M.Wühr induceddissociation (CID) conditions prior to peptide fragmen- Department of Molecular Biology and tation. In addition, an alkyne unit allows an enrichment moiety, the Lewis-Sigler Institute for Integrative Genomics, Princeton University for example, biotin, to be attached to the crosslinked sites Washington Road,Princeton, NJ 08544 (USA) with the helpofCuAACreaction.[19] [+] These authors contributed equally to this work. Application of the crosslinker can follow the workflowde- Supporting information and the ORCID identification numbers for the authors of this article can be found under https://doi.org/10.1002/ picted in Figure 1B.Itinvolves the addition of reagent 1 to a cbic.201900611. complex proteome, fixing the native state distance information 2019 The Authors. Published by Wiley-VCH Verlag GmbH&Co. KGaA. of peptides in close proximity and preserving them throughout This is an open access article under the terms of the Creative Commons At- the further workflowfor MS analysis. Attachment of the affinity tributionNon-Commercial License,whichpermitsuse, distributionand re- group for enrichmentisperformed after crosslinking to avoid production in any medium, provided the original work is properly cited and is not used for commercial purposes. interference from bulky enrichmentgroups. By modification of This article is part of aSpecial Issue commemorating the 20th Anniversary the crosslinked peptides at the protein level, excess small-mol- of ChemBioChem. To view the complete issue, visit our homepage ecule reagents can readily be removed by acetone precipita- ChemBioChem 2020, 21,103 –107 103 2019 The Authors. PublishedbyWiley-VCH Verlag GmbH &Co. KGaA, Weinheim Communications to aclean separation of the peptides (a, b)and generates two fragments foreach peptide:analkene and asulfenic acid frag- ment;the latter formsathial upon water loss. This provides two mass pairs with acharacteristic Dm/z 32. Importantly,we observed that fragmentation pathway a(Figure 1C)predomi- nated.Therefore, for the a-peptide the alkene fragment, and for the b-peptide the thial fragment, are the main cleavage products.Due to the asymmetric cleavage properties, mostof the signal intensity is retained on one fragment per peptide, which should provide excellent sensitivity in MS3 experiments. The synthesis of reagent 1 is straightforward(Scheme1). The startingpoint is the oxidised disulfide dimer of homocys- tein 2,which is treatedwith 4-pentynoic acid to give disulfide Scheme1.Synthesis of cliXlink (1). a) 4-Pentynoicacid, N-(3-dimethylamino- propyl)-N’-ethylcarbodiimide hydrochloride (EDC·HCl), 1-hydroxybenzotri- azole hydrate (HOBt·H2O), NEt3,DMF,RT, 15 h, 71%; b) over two steps: 1) tris(2-carboxyethyl)phosphine hydrochloride (TCEP·HCl), NaHCO3, DMF, H2O, RT,3h; 2) methyl 3-bromopropionate, 45 8C, 44 h, 55%; c) LiOH,THF, H2O, 08CRT, overnight (o/n), 91%; d) N-hydroxysuccinimide (NHS), pyridine, Figure 1. A) Structureof1.Su: succinimidyl. B) Workflowfor XL-MS experi- trifluoroacetic anhydride,MeCN, 08CRT, o/n, 78%; e) meta-chloroperoxyben- ments. After the addition of 1,protein sites in close proximity are covalently zoic acid (mCPBA), AcOEt,RT, 30 min,57%. linked.The generated crosslinks can be functionalised with acopper-cata- lysed Huisgenreaction (CuAAC). Excess reagents are removed by acetone precipitations. After enzymaticdigestionand enrichment on magnetic strep- tavidin beads,crosslinkedpeptides were cleavedoff under mild conditions 3.Reductivecleavage of the disulfide and alkylation of the and subsequently analysed by means of LC-MS2.C)Fragmentation pathways generated thiols with methyl 3-bromopropionate generates of the crosslinked peptides,forming two peptidepairs with acharacteristic sulfide compound 4.Saponification of both methyl esters to 5 Dm of 31.9721 u. rep and conversionof5 into activated bissuccinimidylester 6,fol- lowed by oxidation of the thioether to the sulfoxide, gives re- tion. This is followed by enzymatic digestionofthe proteins. agent 1 in atotal yield of 16 %. Of particularimportance is that The crosslinkedpeptides are in this way labelled, for example, the reagent is very pure and the reactive ester units are in with biotin, whichallows for their enrichment. Afterwards, they place at both sides. Partial hydrolysis needs to be avoided. This are analysed by means of mass spectrometry.Because the indi- was ensured by afinal precipitation purification.Reagent 1 vidual peptidemasses in acrosslink are not immediately acces- was dissolved in amixture of ethyl acetate and dichlorometh- sible, crosslink assignment is difficult, especially in complex ane and precipitated upon addition of hexanes. samples. This requires the use of MS-cleavable reagents,which We next investigated the MS properties of 1.Tothis end, we facilitateMS2 identification by forming specific fragment added 1 to the commonly used modelprotein,bovine serum ions.[20,21] At best, the reagent should also enable MS3 experi- albumin(BSA). We followed the workflow depicted in Fig- ments,which requires that the crosslinker is cleaved before ure 1B withoutperforming the enrichmentstep. In short,after the peptides. This allows peptides to be separated for individu- the addition of 1 to the protein solution and reaction for 1h al MS3-based identification. Our reagent 1 contains b-hydrogen at room temperature and physiological pH, we precipitated atoms on both sides of the sulfoxide, so that fragmentation the protein with acetone,
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