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Tyrosine nitration of human ERK1 introduces an intra-hydrogen bond by molecular dynamics simulations

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Abstract

ERK1 is an important kinase in Ras–Raf–MEK signaling. We have recently demonstrated by mass spectrometry that Tyr210 of ERK1 can be nitrated, and the nitration leads to a novel CHIP–dependent ERK1 degradation pathway. This motivated us to investigate the effect of this nitration on local and global structures of human ERK1 by Gaussian calculations and molecular dynamics simulations. Our study shows that the nitration at either the CE1 or the CE2 positions introduces an intra-hydrogen bond between the hydroxyl group and the nitro group of the nitrated Tyr210 of ERK1. Our data indicate that the hydrogen bond between Tyr210 and Glu237 is not stable and the nitration of Tyr210 facilitates its breakage. The previous studies demonstrated that ERK1 can be autophosphorylated at tyrosine residue 204. We next studied the effect of the phosphorylation in combination with the nitration. We found that the nitration of Tyr210 modestly decreases its inter-residue electrostatic interactions, and the phosphorylation of Tyr204 increases its inter-residue electrostatic interactions as expected. In the active state of ERK1, the conserved Lys71 forms a salt bridge with the conserved Glu88 and this salt bridge is essential for the activity of ERK1. Our data demonstrate an additional salt bridge for Glu88 with Arg84, and this salt bridge is unphosphorylation-dependent. The phosphorylation of ERK1 with the nitration at CE2, not at CE1, slightly enhances the K71–E88 salt bridge. Collectively, our simulations have demonstrated formation of a tyrosine nitration–dependent hydrogen bond. Our molecular dynamics simulations in combination with the experimental data on the nitration of Tyr210 of ERK1 indicate that a post-translational modification of a protein can specifically alter local structural environments, and a local structural change could lead to changes of protein functions.

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Acknowledgments

The authors thank the comments from Dr. Perkins on this study. The authors also thank the support from University Undergraduate Research Mini-Grant and STEP Awards and the equipment [LEQSF(2015-16)-ENH-TR-34] and software [LEQSF(2017-18)-ENH-TR-31] support from the Enhancement Program of Louisiana Board of Regents. The molecular dynamics simulations and Gaussian calculations of human ERK1 were conducted with high-performance computational resources provided by the Louisiana Optical Network Initiative (LONI) (http://www.loni.org).

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Authors and Affiliations

  1. Department of Chemistry, University of Louisiana at Lafayette, Lafayette, LA, 70504, USA

    Wu Xu, Oliver Y. Achi, Kathleen D. Knierim & Justin G. Hanks

  2. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Rd., Beijing, 100101, China

    Yuanya Zhang & Yingchun Wang

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  1. Wu Xu
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Correspondence to Wu Xu or Yingchun Wang.

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Xu, W., Zhang, Y., Achi, O.Y. et al. Tyrosine nitration of human ERK1 introduces an intra-hydrogen bond by molecular dynamics simulations. Struct Chem 30, 1459–1470 (2019). https://doi.org/10.1007/s11224-019-01306-z

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