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DOI: 10.1002/open.201200038 Does Electron Capture Dissociation Cleave Protein Disulfide Bonds? Barbara Ganisl and Kathrin Breuker* [a] Introduction Over the past two decades , mass spectrometry (MS) became centr al to the iden tific ation and charac teriza tion of prote ins and their posttranslational modifications. Among the latter, di- sul fid e bonds are of particular importance as the ir cov ale nt R 1 À S ÀS ÀR 2 linkages can substantially stabilize a protein’s fold against denaturation. [1] However, disulfide bonds can also seri- ously complica te sequence analysis using MS by preventing fragment ion separation in protein dissociation experiments. [2] Electron capture dissociation (ECD), introduced by McLaffer- ty and coworkers in 1998, [3] revolutionized peptide and protein MS by providing far more extensive sequence coverage [4] than convention al dissoc iation metho ds based on ‘slow ion heat- ing’, [5] such as collisionally activated dissociation (CAD). A year later, in 1999, the McLafferty group published a study in which it was concluded that disulfide bond cleavage is preferred over backbone cleav age into c and compl ement ary z fragments (Scheme 1) in ECD of peptid es and protei ns. [6] The propos ed mechanism for disulfide bond clea vage involves a mobil e H atom and its transfer to the disul fide bond. Although thi s study is highly cited (320 times, as of November 2012), and the proposed mechanism deb ated, little exp eri mental data has since provided conclusive evidence for preferential cleavage of disulfide bonds in ECD or its closely related descendant, elec- tron transfer dissociation (ETD). [7] Here, we reinvestigate by ex- periment the question of whether or not, and how, protein di- sul fide bonds are cle aved during ECD. Our comprehensive study has impor tant implicati ons for protein dissoc iation ex- periments using ECD or ETD, and their as yet debated mecha- nisms. Results Thi s study was sparke d by an obse rva tio n tha t appear ed to contradict the hypothesis of preferential disulfide bond cleav- age in ECD. Specifically, in ECD of the protein ecotin, we found c and z fragments from backbone cleavage exclusively in re- gions that are not bridged by its disulfide bond. To further in- ves tigate thi s phenomenon, we have studied the dis ulfide- bonded proteins, trypsin inhibi tor , insulin, aprotinin, and the peptides K8- and R8-vasopressin by ECD, with and without vi- brational excitation by collisions and infrared (IR) laser heating before and after electron capture, respectively. Pep tid e and protein cha rac ter ization by mass spectrometry (MS) relies on their dissociation in the gas phase into specific fragments whose mass values can be aligned as ‘mass ladders’ to provide sequence information and to localize possible post- tra nsl ati ona l mod ifi cat ions. The most common dis soci ati on method involv es slow heating of even-electron ( M + n H) n + ions from elect rospray ionizatio n by ener getic collisions with inert gas , and cleavage of ami de backbone bonds. More re- cen tly , dis soc iation methods based on electron capture or transf er were found to provid e far more extensive sequence coverage through uns ele ctive cleavage of backbone NÀ Ca bonds. As another important feature of electron capture disso- cia tion (ECD) and ele ctron tra nsf er dis soci ati on (ETD), the ir unique unimolecular radical ion chemistry generally preserves labile posttranslational modifications such as glycosylation and phospho ryl ati on. Mor eov er , it was post ula ted tha t dis ulf ide bond cleavage is preferred over backbone cleavage, and that capture of a single electron can break both a backbone and a dis ulf ide bond, or even two disul fide bonds between two peptide chains. However, the proposal of preferential disulfide bond cleavage in ECD or ETD has recently been debated. The experimental data presented here reveal that the mechanism of protein disulfide bond cleavage is much more intricate than previously anticipated. Scheme 1. Proposed mechanism for c and z fragment formation in ECD. [3] [a] B. Ganisl, Dr. K. Breuker Institute for Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI) University of Innsbruck Innrain 80–82, 6020 Innsbruck (Austria) E-mail: [email protected] Homepage: http://www.bioms-breuker .at/  2012 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 260 2012 The Authors. Published by Wiley-VCH V erlag GmbH & Co. KGaA, Weinheim ChemistryOpen 2012  , 1, 260 – 268

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