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Nitric Oxide Modulates Endonuclease III Redox Activity by a 800 Mv Negative Shift Upon [Fe4s4] Cluster Nitrosylation Levi A

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Nitric Oxide Modulates Endonuclease III Redox Activity by a 800 Mv Negative Shift Upon [Fe4s4] Cluster Nitrosylation Levi A Subscriber access provided by Caltech Library Article Nitric Oxide Modulates Endonuclease III Redox Activity by a 800 mV Negative Shift upon [Fe4S4] Cluster Nitrosylation Levi A. Ekanger, Paul H. Oyala, Annie Moradian, Michael J. Sweredoski, and Jacqueline K. Barton J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07362 • Publication Date (Web): 26 Aug 2018 Downloaded from http://pubs.acs.org on August 27, 2018 Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. 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ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts. is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties. Page 1 of 12 Journal of the American Chemical Society 1 2 3 4 5 6 7 Nitric Oxide Modulates Endonuclease III Redox Activity by a 800 mV Nega- 8 tive Shift upon [Fe4S4] Cluster Nitrosylation 9 10 Levi A. Ekanger,1 Paul H. Oyala,1 Annie Moradian,2 Michael J. Sweredoski,2 and Jacqueline K. Barton1* 11 12 1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 13 2Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA 91125 14 15 16 ABSTRACT: Here we characterize the [Fe4S4] cluster nitrosylation of a DNA repair enzyme, Endonuclease III (EndoIII), using DNA- 17 modified gold electrochemistry and protein film voltammetry, electrophoretic mobility shift assays, mass spectrometry of whole and trypsin- 18 digested protein, and a variety of spectroscopies. Exposure of EndoIII to nitric oxide under anaerobic conditions transforms the [Fe4S4] clus- – 19 ter into a dinitrosyl iron complex, [(Cys)2Fe(NO)2] , and Roussin’s red ester, [(µ-Cys)2Fe2(NO)4], in a 1:1 ratio with an average retention of 20 3.05 ± 0.01 Fe per nitrosylated cluster. The formation of the dinitrosyl iron complex is consistent with previous reports, but the Roussin’s red 21 ester is an unreported product of EndoIII nitrosylation. Hyperfine sublevel correlation (HYSCORE) pulse EPR spectroscopy detects two 14 22 distinct classes of NO with N hyperfine couplings consistent with the dinitrosyl iron complex and reduced Roussin’s red ester. Whole- 14 15 23 protein mass spectrometry of EndoIII nitrosylated with NO and NO support the assignment of a protein-bound [(µ-Cys)2Fe2(NO)4] 2+/3+ 24 Roussin’s red ester. The [Fe4S4] redox couple of DNA-bound EndoIII is observable using DNA-modified gold electrochemistry, but ni- 25 trosylated EndoIII does not display observable redox activity using DNA electrochemistry on gold despite having a similar DNA-binding 26 affinity as the native protein. However, direct electrochemistry of protein films on graphite reveals the reduction potential of native and nitro- sylated EndoIII to be 127 ± 6 and –674 ± 8 mV vs NHE, respectively, corresponding to a shift of approximately –800 mV with cluster nitro- 27 sylation. Collectively, these data demonstrate that DNA-bound redox activity, and by extension DNA-mediated charge transport, is modulat- 28 ed by [Fe4S4] cluster nitrosylation. 29 30 31 32 INTRODUCTION 33 Nitric oxide (NO) is an endogenous reactive nitrogen species 34 that plays an important role in homeostatic regulation,1–3 cytopro- 35 tective and cytotoxic pathways,4–6 tumor progression,7–10 and bio- 36 film dispersal.11 NO often elicits a response by coordinating metal 37 centers of metalloenzymes, such as in heme nitrosylation of soluble 38 guanylyl cyclase during vasodilation.12 Non-heme Fe centers are 39 also prone to nitrosylation. For example, the transcription factors 40 SoxR, NsrR, and FNR each contain a [Fe2S2] or [Fe4S4] cluster that 13–17 41 react with NO. The [Fe4S4] clusters in transcription factors 42 often play a functional role by modulating protein conformation 43 which, in turn, modulates DNA-binding affinity and gene expres- 17 44 sion. Nitrosylation of iron–sulfur clusters typically results in pro- tein-bound iron nitrosyl species such as the relatively common 45 – 18–20 dinitrosyl iron complex, [(Cys)2Fe(NO)2] . However, there is 46 growing evidence that other iron nitrosyl species, such as the Rous- 47 sin’s red ester, [(µ-Cys)2Fe2(NO)4], a structural analogue of the red 48 2+ iron nitrosyl salt reported by Roussin in 1858 (Figure 1),21 are more Figure 1. Structure of a protein-bound [Fe4S4] cluster, dinitrosyl iron 49 common than previously thought.22–26 While recent studies have complex, Roussin’s red ester, and the Roussin’s red salt anion. 50 focused on the nitrosylation of transcription factors, the [Fe4S4] The [Fe4S4] clusters in DNA repair enzymes were once thought 51 clusters of DNA repair enzymes, such as Endonuclease III (En- to be strictly structural motifs based on their relatively positive 52 27,28 doIII) and DinG, are also targets for NO reactivity. reduction potential. However, upon binding DNA, the close prox- 53 imity of the polyanionic phosphate backbone negatively shifts the 54 2+/3+ [Fe4S4] midpoint potential to approximately 80 mV vs normal 55 hydrogen electrode (NHE) thereby activating its redox activity in 56 the DNA-bound form.29–31 Our laboratory has proposed that redox 2+ 3+ 57 signaling between DNA-bound [Fe4S4] and [Fe4S4] clusters, 58 utilizing DNA-mediated charge transport (DNA CT), facilitates 32 59 efficient DNA lesion detection. Given the importance of [Fe4S4] 60 ACS Paragon Plus Environment Journal of the American Chemical Society Page 2 of 12 clusters for DNA CT in biology and their propensity to react with exclusion column. Experiments and successive dilutions or concen- 1 NO, we are interested in studying how NO affects DNA CT by trations were performed using filtrate collected after size-exclusion 2 cluster nitrosylation. purification. 3 Our laboratory has explored DNA CT using EndoIII in Esche- UV–Vis, Circular Dichroism, and CW EPR Spectroscopies. UV– 4 richia coli as a model [Fe4S4] cluster DNA repair enzyme. The vis data were acquired using either a Cary 100 Bio (Agilent) or 5 [Fe4S4] cluster of EndoIII reacts with NO, leading to inactivation of DeNovix DS-C spectrophotometer. Circular dichroism spectros- 27 6 DNA repair. However, [Fe4S4]cluster nitrosylation of EndoIII has copy was performed using an AVIV Biomedical spectrometer in the 7 not been explored within the context of DNA CT. Here we report Beckman Institute Laser Resource Center. In an anaerobic cham- 8 the effect of EndoIII [Fe4S4] cluster nitrosylation on DNA CT ber, protein collected from size-exclusion purification was diluted 9 using DNA-modified gold electrochemistry, protein film voltam- to 10 µM in a total volume of 800 µL and loaded into rectangular 10 metry, electrophoretic mobility shift assays, mass spectrometry of spectrophotometer cells with 2 mm pathlength (Starna Cells). 11 whole and trypsin-digested protein, and UV–vis, continuous-wave Spectra are normalized to ellipticity minima at 222 nm. 12 (CW) and pulse electron paramagnetic resonance (EPR), and X-band CW-EPR spectroscopy was performed on an EMX X- 13 circular dichroism spectroscopies. We connect our biophysical band spectrometer (Bruker) equipped with an ESR-900 cryogen 14 observations within the DNA CT model to account for the electro- flow cryostat (Oxford) and an ITC-503 temperature controller. 15 chemical consequences of [Fe4S4] cluster nitrosylation. Samples (150 µL each) were loaded into 4 mm thin-wall precision 16 quartz EPR tubes (Wilmad LabGlass, 715-PW-250MM). To re- 17 EXPERIMENTAL SECTION duce dinitrosyl iron and Roussin’s red complexes, nitrosylated En- doIII was incubated with sodium dithionite (1:25 pro- 18 General Procedures. All chemicals were of reagent-grade purity tein/dithionite ratio) for 30 min prior to freezing in liquid nitrogen 19 or better, purchased from Sigma Aldrich unless otherwise noted, while remaining capped under an anaerobic atmosphere. An acqui- 20 and used as received unless otherwise noted. Water was purified on sition temperature of 60 K and microwave power of 0.204 mW 21 a Milli-Q Reference Ultrapure Water Purification System (≥18.2 were used for the ratiometric comparison of double integration 22 MΩ cm). Anaerobic atmospheres (3–4% H2 in N2, ≤1 ppm O2) spin intensities because the iron nitrosyl signals were not saturated 23 were maintained in vinyl chambers using Pd scrubbing towers under these conditions. Signal saturation was evaluated by ensuring 24 (Coy Laboratories). signal intensity grew as the square root of microwave power. Dou- 25 EndoIII Overexpression and Purification. Following reported ble integration spin intensities were measured using Matlab 30 26 procedures, E.
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