This content will become publicly available on June 13, 2020
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:
-
[1];
- SLAC National Accelerator Lab., Menlo Park, CA (United States); Stanford Univ., CA (United States); Univ. of California, San Francisco, CA (United States)
- 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:
Molecular dynamics simulation of triclinic lysozyme in a crystal lattice: Molecular Dynamics of Crystal Lysozyme
journal, June 2015
- Janowski, Pawel A.; Liu, Chunmei; Deckman, Jason
- Protein Science, Vol. 25, Issue 1
X-ray radiation-induced addition of oxygen atoms to protein residues: Visualization of Oxidation and Peroxidation of Protein Residues
journal, July 2016
- Wang, Jimin
- Protein Science, Vol. 25, Issue 8
Very fast empirical prediction and rationalization of protein pKa values
journal, October 2005
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DJ-1, a Novel Oncogene Which Transforms Mouse NIH3T3 Cells in Cooperation withras
journal, February 1997
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- Biochemical and Biophysical Research Communications, Vol. 231, Issue 2
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
DJ-1 as a human oncogene and potential therapeutic target
journal, February 2015
- Cao, Ji; Lou, Siyue; Ying, Meidan
- Biochemical Pharmacology, Vol. 93, Issue 3
Expanding the functional diversity of proteins through cysteine oxidation
journal, December 2008
- Reddie, Khalilah G.; Carroll, Kate S.
- Current Opinion in Chemical Biology, Vol. 12, Issue 6
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
Developing Irreversible Inhibitors of the Protein Kinase Cysteinome
journal, February 2013
- Liu, Qingsong; Sabnis, Yogesh; Zhao, Zheng
- Chemistry & Biology, Vol. 20, Issue 2
Molecular Basis for Redox Activation of Epidermal Growth Factor Receptor Kinase
journal, July 2016
- Truong, Thu H.; Ung, Peter Man-Un; Palde, Prakash B.
- Cell Chemical Biology, Vol. 23, Issue 7
Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies
journal, September 2015
- Bauer, Renato A.
- Drug Discovery Today, Vol. 20, Issue 9
Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress
journal, March 2017
- Bonilha, Vera L.; Bell, Brent A.; Rayborn, Mary E.
- Free Radical Biology and Medicine, Vol. 104
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
Hydrogen peroxide sensing, signaling and regulation of transcription factors
journal, January 2014
- Marinho, H. Susana; Real, Carla; Cyrne, Luísa
- Redox Biology, Vol. 2
PTP1B: a double agent in metabolism and oncogenesis
journal, August 2010
- Yip, Shu-Chin; Saha, Sayanti; Chernoff, Jonathan
- Trends in Biochemical Sciences, Vol. 35, Issue 8
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
Millisecond Radiolytic Modification of Peptides by Synchrotron X-rays Identified by Mass Spectrometry
journal, September 1999
- Maleknia, Simin D.; Brenowitz, Michael; Chance, Mark R.
- Analytical Chemistry, Vol. 71, Issue 18
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
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
Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology
journal, December 2018
- Gehringer, Matthias; Laufer, Stefan A.
- Journal of Medicinal Chemistry, Vol. 62, Issue 12
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
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
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
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
Chemical Probe To Monitor the Parkinsonism-Associated Protein DJ-1 in Live Cells
journal, July 2018
- Drechsel, Jonas; Mandl, Franziska A.; Sieber, Stephan A.
- ACS Chemical Biology, Vol. 13, Issue 8
Discovery and Optimization of Inhibitors of the Parkinson’s Disease Associated Protein DJ-1
journal, July 2018
- Tashiro, Shinya; Caaveiro, Jose M. M.; Nakakido, Makoto
- ACS Chemical Biology, Vol. 13, Issue 9
Isocyanides and cyanides as natural products
journal, October 1992
- Scheuer, Paul J.
- Accounts of Chemical Research, Vol. 25, Issue 10
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
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
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.
- Biochemistry, Vol. 47, Issue 28
Roles of Aspartic Acid-181 and Serine-222 in Intermediate Formation and Hydrolysis of the Mammalian Protein-Tyrosine-Phosphatase PTP1 †
journal, April 1997
- Lohse, Daniel L.; Denu, John M.; Santoro, Nicholas
- Biochemistry, Vol. 36, Issue 15
Rates of thiol-disulfide interchange reactions between mono- and dithiols and Ellman's reagent
journal, January 1977
- Whitesides, George M.; Lilburn, Jennifer E.; Szajewski, Richard P.
- The Journal of Organic Chemistry, Vol. 42, Issue 2
Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate
journal, June 2003
- Salmeen, Annette; Andersen, Jannik N.; Myers, Michael P.
- Nature, Vol. 423, Issue 6941
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