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Title: Shining light on cysteine modification: connecting protein conformational dynamics to catalysis and regulation

Abstract

We report that cysteine is a rare but functionally important amino acid that is often subject to covalent modification. Cysteine oxidation plays an important role in many human disease processes, and basal levels of cysteine oxidation are required for proper cellular function. Because reactive cysteine residues are typically ionized to the thiolate anion (Cys-S -), their formation of a covalent bond alters the electrostatic and steric environment of the active site. X-ray-induced photo-oxidation to sulfenic acids (Cys-SOH) can recapitulate some aspects of the changes that occur under physiological conditions. Here we propose how site-specific cysteine photo-oxidation can be used to interrogate ensuing changes in protein structure and dynamics at atomic resolution. Although this powerful approach can connect cysteine covalent modification to global protein conformational changes and function, careful biochemical validation must accompany all such studies to exclude misleading artifacts. Lastly, new types of X-ray crystallography experiments and powerful computational methods are creating new opportunities to connect conformational dynamics to catalysis for the large class of systems that use covalently modified cysteine residues for catalysis or regulation.

Authors:
ORCiD logo [1];  [2]
  1. SLAC National Accelerator Lab., Menlo Park, CA (United States); Stanford Univ., CA (United States); Univ. of California, San Francisco, CA (United States)
  2. Univ. of Nebraska, Lincoln, NE (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1546912
Grant/Contract Number:  
AC02-76SF00515
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Synchrotron Radiation (Online)
Additional Journal Information:
Journal Name: Journal of Synchrotron Radiation (Online); Journal Volume: 26; Journal Issue: 4; Journal ID: ISSN 1600-5775
Publisher:
International Union of Crystallography
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; cysteine modification; radiation-controlled photo-oxidation; serial X-ray crystallography; enzyme conformational dynamics; molecular dynamics simulations

Citation Formats

van den Bedem, Henry, and Wilson, Mark A. Shining light on cysteine modification: connecting protein conformational dynamics to catalysis and regulation. United States: N. p., 2019. Web. doi:10.1107/s160057751900568x.
van den Bedem, Henry, & Wilson, Mark A. Shining light on cysteine modification: connecting protein conformational dynamics to catalysis and regulation. United States. doi:10.1107/s160057751900568x.
van den Bedem, Henry, and Wilson, Mark A. Thu . "Shining light on cysteine modification: connecting protein conformational dynamics to catalysis and regulation". United States. doi:10.1107/s160057751900568x.
@article{osti_1546912,
title = {Shining light on cysteine modification: connecting protein conformational dynamics to catalysis and regulation},
author = {van den Bedem, Henry and Wilson, Mark A.},
abstractNote = {We report that cysteine is a rare but functionally important amino acid that is often subject to covalent modification. Cysteine oxidation plays an important role in many human disease processes, and basal levels of cysteine oxidation are required for proper cellular function. Because reactive cysteine residues are typically ionized to the thiolate anion (Cys-S-), their formation of a covalent bond alters the electrostatic and steric environment of the active site. X-ray-induced photo-oxidation to sulfenic acids (Cys-SOH) can recapitulate some aspects of the changes that occur under physiological conditions. Here we propose how site-specific cysteine photo-oxidation can be used to interrogate ensuing changes in protein structure and dynamics at atomic resolution. Although this powerful approach can connect cysteine covalent modification to global protein conformational changes and function, careful biochemical validation must accompany all such studies to exclude misleading artifacts. Lastly, new types of X-ray crystallography experiments and powerful computational methods are creating new opportunities to connect conformational dynamics to catalysis for the large class of systems that use covalently modified cysteine residues for catalysis or regulation.},
doi = {10.1107/s160057751900568x},
journal = {Journal of Synchrotron Radiation (Online)},
number = 4,
volume = 26,
place = {United States},
year = {2019},
month = {6}
}

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    Works referencing / citing this record:

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    journal, June 2015

    • Janowski, Pawel A.; Liu, Chunmei; Deckman, Jason
    • Protein Science, Vol. 25, Issue 1
    • DOI: 10.1002/pro.2713

    Very fast empirical prediction and rationalization of protein pKa values
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    • Li, Hui; Robertson, Andrew D.; Jensen, Jan H.
    • Proteins: Structure, Function, and Bioinformatics, Vol. 61, Issue 4
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    DJ-1, a Novel Oncogene Which Transforms Mouse NIH3T3 Cells in Cooperation withras
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    • Nagakubo, Daisuke; Taira, Takahiro; Kitaura, Hirotake
    • Biochemical and Biophysical Research Communications, Vol. 231, Issue 2
    • DOI: 10.1006/bbrc.1997.6132

    Intracellular metal binding and redox behavior of human DJ-1
    journal, December 2017

    • Barbieri, Letizia; Luchinat, Enrico; Banci, Lucia
    • JBIC Journal of Biological Inorganic Chemistry, Vol. 23, Issue 1
    • DOI: 10.1007/s00775-017-1509-5

    DJ-1 as a human oncogene and potential therapeutic target
    journal, February 2015


    Expanding the functional diversity of proteins through cysteine oxidation
    journal, December 2008


    Covalent targeting of acquired cysteines in cancer
    journal, February 2016

    • Visscher, Marieke; Arkin, Michelle R.; Dansen, Tobias B.
    • Current Opinion in Chemical Biology, Vol. 30
    • DOI: 10.1016/j.cbpa.2015.11.004

    Developing Irreversible Inhibitors of the Protein Kinase Cysteinome
    journal, February 2013


    Molecular Basis for Redox Activation of Epidermal Growth Factor Receptor Kinase
    journal, July 2016


    Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress
    journal, March 2017


    Geometric analysis characterizes molecular rigidity in generic and non-generic protein configurations
    journal, October 2015

    • Budday, Dominik; Leyendecker, Sigrid; van den Bedem, Henry
    • Journal of the Mechanics and Physics of Solids, Vol. 83
    • DOI: 10.1016/j.jmps.2015.06.006

    Hydrogen peroxide sensing, signaling and regulation of transcription factors
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    PTP1B: a double agent in metabolism and oncogenesis
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    • Yip, Shu-Chin; Saha, Sayanti; Chernoff, Jonathan
    • Trends in Biochemical Sciences, Vol. 35, Issue 8
    • DOI: 10.1016/j.tibs.2010.03.004

    Radiolytic Modification of Sulfur-Containing Amino Acid Residues in Model Peptides:  Fundamental Studies for Protein Footprinting
    journal, April 2005

    • Xu, Guozhong; Chance, Mark R.
    • Analytical Chemistry, Vol. 77, Issue 8
    • DOI: 10.1021/ac0484629

    Millisecond Radiolytic Modification of Peptides by Synchrotron X-rays Identified by Mass Spectrometry
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    • Maleknia, Simin D.; Brenowitz, Michael; Chance, Mark R.
    • Analytical Chemistry, Vol. 71, Issue 18
    • DOI: 10.1021/ac990500e

    Kinematic Flexibility Analysis: Hydrogen Bonding Patterns Impart a Spatial Hierarchy of Protein Motion
    journal, September 2018

    • Budday, Dominik; Leyendecker, Sigrid; van den Bedem, Henry
    • Journal of Chemical Information and Modeling, Vol. 58, Issue 10
    • DOI: 10.1021/acs.jcim.8b00267

    How Reactive are Druggable Cysteines in Protein Kinases?
    journal, August 2018

    • Awoonor-Williams, Ernest; Rowley, Christopher N.
    • Journal of Chemical Information and Modeling, Vol. 58, Issue 9
    • DOI: 10.1021/acs.jcim.8b00454

    Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology
    journal, December 2018


    qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps
    journal, November 2018

    • van Zundert, Gydo C. P.; Hudson, Brandi M.; de Oliveira, Saulo H. P.
    • Journal of Medicinal Chemistry, Vol. 61, Issue 24
    • DOI: 10.1021/acs.jmedchem.8b01292

    Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors
    journal, November 2018

    • Casimiro-Garcia, Agustin; Trujillo, John I.; Vajdos, Felix
    • Journal of Medicinal Chemistry, Vol. 61, Issue 23
    • DOI: 10.1021/acs.jmedchem.8b01308

    Preferred Hydrogen-Bonding Partners of Cysteine: Implications for Regulating Cys Functions
    journal, September 2016

    • Mazmanian, Karine; Sargsyan, Karen; Grauffel, Cédric
    • The Journal of Physical Chemistry B, Vol. 120, Issue 39
    • DOI: 10.1021/acs.jpcb.6b08109

    Critical Assessment of the Strength of Hydrogen Bonds between the Sulfur Atom of Methionine/Cysteine and Backbone Amides in Proteins
    journal, April 2015

    • Mundlapati, V. Rao; Ghosh, Sanat; Bhattacherjee, Aditi
    • The Journal of Physical Chemistry Letters, Vol. 6, Issue 8
    • DOI: 10.1021/acs.jpclett.5b00491

    Chemical Probe To Monitor the Parkinsonism-Associated Protein DJ-1 in Live Cells
    journal, July 2018


    Discovery and Optimization of Inhibitors of the Parkinson’s Disease Associated Protein DJ-1
    journal, July 2018


    Isocyanides and cyanides as natural products
    journal, October 1992


    Reversible Cysteine Oxidation in Hydrogen Peroxide Sensing and Signal Transduction
    journal, April 2014

    • García-Santamarina, Sarela; Boronat, Susanna; Hidalgo, Elena
    • Biochemistry, Vol. 53, Issue 16
    • DOI: 10.1021/bi401700f

    Thermodynamic and Structural Characterization of the Specific Binding of Zn(II) to Human Protein DJ-1
    journal, April 2014

    • Tashiro, Shinya; Caaveiro, Jose M. M.; Wu, Chun-Xiang
    • Biochemistry, Vol. 53, Issue 14
    • DOI: 10.1021/bi500294h

    Cysteine p K a Depression by a Protonated Glutamic Acid in Human DJ-1
    journal, July 2008

    • Witt, Anna C.; Lakshminarasimhan, Mahadevan; Remington, Benjamin C.
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