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The Cysteine Proteome 13 N Q114 Young-Mi Go, Joshua D Free Radical Biology and Medicine ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 1 Contents lists available at ScienceDirect 2 3 4 Free Radical Biology and Medicine 5 6 journal homepage: www.elsevier.com/locate/freeradbiomed 7 8 9 Review Article 10 11 12 The cysteine proteome 13 n Q114 Young-Mi Go, Joshua D. Chandler, Dean P. Jones 15 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, USA 16 17 18 article info abstract 19 20 Article history: The cysteine (Cys) proteome is a major component of the adaptive interface between the genome and 21 Received 17 November 2014 the exposome. The thiol moiety of Cys undergoes a range of biologic modifications enabling biological 22 Received in revised form switching of structure and reactivity. These biological modifications include sulfenylation and disulfide 23 17 March 2015 formation, formation of higher oxidation states, S-nitrosylation, persulfidation, metalation, and other Accepted 22 March 2015 24 modifications. Extensive knowledge about these systems and their compartmentalization now provides 25 a foundation to develop advanced integrative models of Cys proteome regulation. In particular, detailed Keywords: 26 understanding of redox signaling pathways and sensing networks is becoming available to allow the Cysteine proteome discrimination of network structures. This research focuses attention on the need for atlases of Cys 27 Redox proteome modifications to develop systems biology models. Such atlases will be especially useful for integrative 28 Redox signaling studies linking the Cys proteome to imaging and other omics platforms, providing a basis for improved 29 Functional network Thiol redox-based therapeutics. Thus, a framework is emerging to place the Cys proteome as a complement to 30 Free radicals the quantitative proteome in the omics continuum connecting the genome to the exposome. 31 & 2015 the autors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license 32 (http://creativecommons.org/licenses/by-nc-nd/4.0/). 33 67 34 68 Contents 35 69 36 70 Introduction..............................................................................................................2 37 71 Lessons from the redox proteome . 2 38 72 Centraldogma........................................................................................................ 2 39 Protein thiols exist in a dynamic steady state . 3 73 40 Selective pressure against Cys in protein . 4 74 41 Redox compartmentalization . 4 75 42 Functional networks within the Cys proteome . 5 76 43 Cys proteome chemistry and functions . 6 77 44 Chemical properties of cysteinyl sulfur . 6 78 45 Reactions of protein Cys thiol. 6 79 46 Factors affecting protein thiol reactivity . 6 80 47 The role of Cys in catalytic sites of enzymes . 7 81 Protein Cys redox regulation . 8 48 82 TrxandGSHsystems.................................................................................................. 8 49 83 Regulation of actin cytoskeleton proteins . 9 50 Cys proteome in nuclear protein trafficking ............................................................................... 10 84 51 Nuclear functions of the Cys proteome . 10 85 52 Oxidation of the Cys proteome by H2O2 and derivative species . 10 86 53 H2O2 .........................................................................................................10 87 54 Oxidant species derived from H2O2 .................................................................................12 88 55 S-nitrosylation . 12 89 56 Persulfidation ....................................................................................................... 12 90 57 Alkylation .......................................................................................................... 13 91 58 Integrated function of the Cys proteome . 13 92 59 93 60 94 61 95 n 62 Corresponding author. Fax: þ404 712 2974. 96 63 E-mail address: [email protected] (D.P. Jones). 97 64 http://dx.doi.org/10.1016/j.freeradbiomed.2015.03.022 98 65 0891-5849/& 2015 the autors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 99 66 Please cite this article as: Go, Y-M; et al. The cysteine proteome. Free Radic. Biol. Med. (2015), http://dx.doi.org/10.1016/j. freeradbiomed.2015.03.022i 2 Y.-M. Go et al. / Free Radical Biology and Medicine ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 1 Perspective and future directions. 13 67 2 Acknowledgments. 14 68 3 References.............................................................................................................. 14 69 4 70 5 71 6 72 7 73 8 Introduction challenge also provided sensing and signaling systems for tem- 74 9 poral and spatial execution of differentiation and development in 75 10 The sulfur atom of cysteine (Cys) provides a considerable range multicellular organisms. 76 fl 11 of chemical reactivity and structural exibility in the proteome. In the present review of the Cys proteome, we start with a 77 12 The presence of conserved Cys in motifs of proteins found in summary of lessons learned from study of the redox proteome, 78 13 essentially all life forms indicates that these chemical character- that portion of reversible and irreversible covalent modifications 79 14 istics were harnessed in early evolution to support enzyme that link redox metabolism to biologic structure and function [1]. 80 15 catalysis, transcriptional regulation, protein folding, and three- We follow this with a more specific consideration of the chemistry 81 16 dimensional structure. A remarkable range of biologic functions is of sulfur and the spectrum of oxidative reactions that defines Cys 82 17 supported by Cys because sulfur is stable in multiple coordinate proteomic functions. In a third section, we address the redox 83 18 covalent bonds with the major atoms of living organisms (C, H, O, regulation systems, especially focusing on major reducing systems 84 19 N, P), forms stable coordinate complexes with transition metal that balance the oxidative reactions and support a rapidly evolving 85 – – 20 ions (Zn, Fe, Cu), and is stable at a range of oxidation states ( SH, understanding of the spatiotemporal nature of redox regulation. In 86 – – À1 – À1 21 SS , SO2 , SO3 ). Additionally, Cys thiols differentially undergo this, we provide specific examples illustrating the organizational 87 22 reversible ionization to the negatively charged thiolate form over structure of stable, kinetically controlled functional redox net- 88 fl 23 the physiologic range of pH to exibly optimize the functions of works and summarize other modifications such as S-nitrosylation 89 fi 24 speci c peptidyl Cys. and persulfidation. Finally, we discuss the Cys proteome within the 90 25 The human genome encodes about 214,000 Cys. Cys is widely context of integrated omics approaches, highlighting the ongoing 91 26 distributed among proteins, with most expressing at least one and need for development of quantitative redox biology models. 92 27 many having multiple coordinated Cys and Cys-rich domains. The 93 28 reactivity and diverse functions of Cys are mirrored by a spectrum 94 29 of susceptibilities and dysfunctions of their respective proteins, Lessons from the redox proteome 95 30 resulting in central roles of the Cys proteome in development, 96 31 signal transduction, biologic defenses, aging, and disease. Con- Central dogma 97 32 siderable knowledge has accumulated for the symptoms and 98 33 etiology of major human diseases, such as cardiovascular disease, Cys is incorporated into protein as the thiol (RSH) form, with 99 34 Alzheimer disease, lung disease, metabolic syndrome, eye disease, apparently no exception. Thiols are oxidized to sulfenic acids 100 35 and diseases of other organ systems. These often share related (RSOÀ) intermediate to formation of disulfides (RSSR) and higher 101 oxidative phenotypes and mechanisms, and progress in redox À 36 oxidation states (e.g., RSO2 ). Thiols and disulfides also undergo 102 37 systems biology is beginning to provide an understanding of the exchange reactions in which the thiol reacts to form a new 103 integration of the underlying redox systems. 38 disulfide and liberates a different thiol (RSH þ R1SSR1 2 RSSR1 104 Early photosynthetic organisms transformed the earth by fixing 39 þ R1SH) [5]. Disulfide is a common posttranslational modification 105 40 the carbon atom of CO2 into hydrocarbons and releasing bound for three-dimensional structure, as a component of multistep 106 41 atomic oxygen as gaseous molecular O2. This changed the atmo- vectorial processing and transport, as a switching mechanism in 107 o 42 sphere from 1% to about 21% O2 and had a profound effect on regulation or signaling, and as a consequence of oxidative stress. 108 43 life forms by creating a diversity of external environments with Research with redox Western- and mass spectrometry-based 109 44 different oxidative conditions. Contemporary redox proteomic redox proteomics methods shows that partial oxidation is com- 110 45 systems have evolved as a result of the selective pressures of an mon for Cys residues throughout the proteome of mammalian 111 46 oxygen environment and aerobic respiration, with extant genomes systems [6–10]. This contradicts earlier interpretations that Cys 112 47 having selectively advantageous redox proteomic structures that thiol oxidation represents only an artifact of extraction [11] and 113 48 protect the genome and ensure its replication despite environ- supports the hypothesis
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