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Human γS-Crystallin–Copper Binding Helps Buffer against Aggregation Caused by Oxidative Damage

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Download Hi-Res ImageDownload to MS-PowerPointCite This:Biochemistry 2020, 59, 25, 2371-2385
    Article

    Human γS-Crystallin–Copper Binding Helps Buffer against Aggregation Caused by Oxidative Damage
    Click to copy article linkArticle link copied!

    • Kyle W. Roskamp
      Kyle W. Roskamp
      Department of Chemistry, University of California, Irvine, California 92697-2025, United States
      More by Kyle W. Roskamp
    • Sana Azim
      Sana Azim
      Max Planck Institute for the Structure and Dynamics of Matter, Center for Free Electron Laser Science, Luruper Chaussee 149, Hamburg 22761, Germany
      More by Sana Azim
    • Günther Kassier
      Günther Kassier
      Max Planck Institute for the Structure and Dynamics of Matter, Center for Free Electron Laser Science, Luruper Chaussee 149, Hamburg 22761, Germany
      More by Günther Kassier
    • Brenna Norton-Baker
      Brenna Norton-Baker
      Department of Chemistry, University of California, Irvine, California 92697-2025, United States
      Max Planck Institute for the Structure and Dynamics of Matter, Center for Free Electron Laser Science, Luruper Chaussee 149, Hamburg 22761, Germany
      More by Brenna Norton-Baker
    • Marc A. Sprague-Piercy
      Marc A. Sprague-Piercy
      Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, United States
      More by Marc A. Sprague-Piercy
    • R. J. Dwyane Miller
      R. J. Dwyane Miller
      Max Planck Institute for the Structure and Dynamics of Matter, Center for Free Electron Laser Science, Luruper Chaussee 149, Hamburg 22761, Germany
      Departments of Chemistry and Physics, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada
      More by R. J. Dwyane Miller
      Orcidhttp://orcid.org/0000-0003-0884-0541
    • Rachel W. Martin*
      Rachel W. Martin
      Department of Chemistry, University of California, Irvine, California 92697-2025, United States
      Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, United States
      *Email: [email protected]
      More by Rachel W. Martin
      Orcidhttp://orcid.org/0000-0001-9996-7411
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    Biochemistry

    Cite this: Biochemistry 2020, 59, 25, 2371–2385
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.biochem.0c00293
    Published June 8, 2020
    Copyright © 2020 American Chemical Society
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    Abstract

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    Divalent metal cations can play a role in protein aggregation diseases, including cataract. Here we compare the aggregation of human γS-crystallin, a key structural protein of the eye lens, via mutagenesis, ultraviolet light damage, and the addition of metal ions. All three aggregation pathways result in globular, amorphous-looking structures that do not elongate into fibers. We also investigate the molecular mechanism underlying copper(II)-induced aggregation. This work was motivated by the observation that zinc(II)-induced aggregation of γS-crystallin is driven by intermolecular bridging of solvent-accessible cysteine residues, while in contrast, copper(II)-induced aggregation of this protein is exacerbated by the removal of solvent-accessible cysteines via mutation. Here we find that copper(II)-induced aggregation results from a complex mechanism involving multiple interactions with the protein. The initial protein–metal interactions result in the reduction of Cu(II) to Cu(I) with concomitant oxidation of γS-crystallin. In addition to the intermolecular disulfides that represent a starting point for aggregation, intramolecular disulfides also occur in the cysteine loop, a region of the N-terminal domain that was previously found to mediate the early stages of cataract formation. This previously unobserved ability of γS-crystallin to transfer disulfides intramolecularly suggests that it may serve as an oxidation sink for the lens after glutathione levels have become depleted during aging. γS-Crystallin thus serves as the last line of defense against oxidation in the eye lens, a result that underscores the chemical functionality of this protein, which is generally considered to play a purely structural role.

    Copyright © 2020 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.biochem.0c00293.

    • Additional TEM images and characterization data for the γS-crystallin aggregates; FTIR spectra, SEC and SDS–PAGE data, and mass spectrometry data; a figure showing potential ion-binding sites; and tables of literature data for the cysteine content of human crystallin proteins (PDF)

    Accession Codes

    Human γS-crystallin, Uniprot CRYGS_HUMAN, PDB entries 2M3T and 6FD8; Mus musculus (mouse) γS-crystallin, PDB entry 6MY8.

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    Click to copy section linkSection link copied!

    This article is cited by 21 publications.

    1. Martin E. Tovar-Ramírez, Nils Schuth, Oscar Rodríguez-Meza, Thomas Kroll, Gloria Saab-Rincon, Miguel Costas, Kirsten Lampi, Liliana Quintanar. ATCUN-like Copper Site in βB2-Crystallin Plays a Protective Role in Cataract-Associated Aggregation. Inorganic Chemistry 2023, 62 (27) , 10592-10604. https://doi.org/10.1021/acs.inorgchem.3c00794
    2. Giovanni Palomino-Vizcaino, Nils Schuth, José A. Domínguez-Calva, Oscar Rodríguez-Meza, Eduardo Martínez-Jurado, Eugene Serebryany, Jonathan A. King, Thomas Kroll, Miguel Costas, Liliana Quintanar. Copper Reductase Activity and Free Radical Chemistry by Cataract-Associated Human Lens γ-Crystallins. Journal of the American Chemical Society 2023, 145 (12) , 6781-6797. https://doi.org/10.1021/jacs.2c13397
    3. Brenna Norton-Baker, Megan A. Rocha, Jessica Granger-Jones, Dmitry A. Fishman, Rachel W. Martin. Human γS-Crystallin Resists Unfolding Despite Extensive Chemical Modification from Exposure to Ionizing Radiation. The Journal of Physical Chemistry B 2022, 126 (3) , 679-690. https://doi.org/10.1021/acs.jpcb.1c08157
    4. Zhan Gao, Lei Li, Weiwei Chen, Zihan Ma, Yuan Li, Yuanji Gao, Chuan-Fan Ding, Xiaoyong Zhao, Yuanjiang Pan. Distinguishment of Glycan Isomers by Trapped Ion Mobility Spectrometry. Analytical Chemistry 2021, 93 (26) , 9209-9217. https://doi.org/10.1021/acs.analchem.1c01461
    5. Ales Cvekl, Jan Vijg. Aging of the eye: Lessons from cataracts and age-related macular degeneration. Ageing Research Reviews 2024, 99 , 102407. https://doi.org/10.1016/j.arr.2024.102407
    6. Eugene Serebryany, Rachel W. Martin, Gemma R. Takahashi. The Functional Significance of High Cysteine Content in Eye Lens γ-Crystallins. Biomolecules 2024, 14 (5) , 594. https://doi.org/10.3390/biom14050594
    7. Oscar Rodríguez-Meza, Giovanni Palomino-Vizcaino, Liliana Quintanar, Miguel Costas. Mercury ions impact the kinetic and thermal stabilities of human lens γ-crystallins via direct metal-protein interactions. Journal of Inorganic Biochemistry 2023, 242 , 112159. https://doi.org/10.1016/j.jinorgbio.2023.112159
    8. Daisy Shu, Suman Chaudhary, Kin-Sang Cho, Anton Lennikov, William Miller, David Thorn, Menglu Yang, Tina McKay. Role of Oxidative Stress in Ocular Diseases: A Balancing Act. Metabolites 2023, 13 (2) , 187. https://doi.org/10.3390/metabo13020187
    9. Krishna Mohan Poluri, Khushboo Gulati, Deepak Kumar Tripathi, Nupur Nagar. Protein Networks in Human Disease. 2023, 1-41. https://doi.org/10.1007/978-981-99-2423-3_1
    10. Yanahi Posadas, Carolina Sánchez-López, Liliana Quintanar. Copper binding and protein aggregation: a journey from the brain to the human lens. RSC Chemical Biology 2023, 25 https://doi.org/10.1039/D3CB00145H
    11. Roy A. Quinlan, Frank Giblin. The eye lens as an aging paradigm par excellence. Experimental Eye Research 2022, 218 , 109003. https://doi.org/10.1016/j.exer.2022.109003
    12. Brenna Norton-Baker, Pedram Mehrabi, Ashley O. Kwok, Kyle W. Roskamp, Megan A. Rocha, Marc A. Sprague-Piercy, David von Stetten, R.J. Dwayne Miller, Rachel W. Martin. Deamidation of the human eye lens protein γS-crystallin accelerates oxidative aging. Structure 2022, 30 (5) , 763-776.e4. https://doi.org/10.1016/j.str.2022.03.002
    13. Vanesa Ramirez-Bello, Javier Martinez-Seoane, Arline Fernández-Silva, Carlos Amero. Zinc and Copper Ions Induce Aggregation of Human β-Crystallins. Molecules 2022, 27 (9) , 2970. https://doi.org/10.3390/molecules27092970
    14. Naouel Gharbi, Dagne Røise, Jorunn-Elise Førre, Amanda J. Edson, Helena A. Hushagen, Valentina Tronci, Ann-Kristin Frøyset, Kari E. Fladmark. Reintroduction of DJ-1 in Müller Cells Inhibits Retinal Degeneration in the DJ-1 Deficient Retina. Antioxidants 2021, 10 (12) , 1862. https://doi.org/10.3390/antiox10121862
    15. Eugene Serebryany, David C. Thorn, Liliana Quintanar. Redox chemistry of lens crystallins: A system of cysteines. Experimental Eye Research 2021, 211 , 108707. https://doi.org/10.1016/j.exer.2021.108707
    16. May T. Maung, Alyssa Carlson, Monserrat Olea‐Flores, Lobna Elkhadragy, Kyle M. Schachtschneider, Napoleon Navarro‐Tito, Teresita Padilla‐Benavides. The molecular and cellular basis of copper dysregulation and its relationship with human pathologies. The FASEB Journal 2021, 35 (9) https://doi.org/10.1096/fj.202100273RR
    17. Brenna Norton-Baker, Pedram Mehrabi, Juliane Boger, Robert Schönherr, David von Stetten, Hendrik Schikora, Ashley O. Kwok, Rachel W. Martin, R. J. Dwayne Miller, Lars Redecke, Eike C. Schulz. A simple vapor-diffusion method enables protein crystallization inside the HARE serial crystallography chip. Acta Crystallographica Section D Structural Biology 2021, 77 (6) , 820-834. https://doi.org/10.1107/S2059798321003855
    18. Gianluca Arauz-Garofalo, Meritxell Jodar, Mar Vilanova, Alberto de la Iglesia Rodriguez, Judit Castillo, Ada Soler-Ventura, Rafael Oliva, Marta Vilaseca, Marina Gay. Protamine Characterization by Top-Down Proteomics: Boosting Proteoform Identification with DBSCAN. Proteomes 2021, 9 (2) , 21. https://doi.org/10.3390/proteomes9020021
    19. Megan A. Rocha, Marc A. Sprague‐Piercy, Ashley O. Kwok, Kyle W. Roskamp, Rachel W. Martin. Chemical Properties Determine Solubility and Stability in βγ‐Crystallins of the Eye Lens. ChemBioChem 2021, 22 (8) , 1329-1346. https://doi.org/10.1002/cbic.202000739
    20. Alexia A. Kalligeraki, Roy A. Quinlan. Structural Proteins | Crystallins of the Mammalian Eye Lens. 2021, 639-667. https://doi.org/10.1016/B978-0-12-819460-7.00139-0
    21. Calvin J. Vetter, David C. Thorn, Samuel G. Wheeler, Charlie C. Mundorff, Kate A. Halverson, Thomas E. Wales, Ujwal P. Shinde, John R. Engen, Larry L. David, John A. Carver, Kirsten J. Lampi. Cumulative deamidations of the major lens protein γS ‐crystallin increase its aggregation during unfolding and oxidation. Protein Science 2020, 29 (9) , 1945-1963. https://doi.org/10.1002/pro.3915
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    Biochemistry

    Cite this: Biochemistry 2020, 59, 25, 2371–2385
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.biochem.0c00293
    Published June 8, 2020
    Copyright © 2020 American Chemical Society
    Request reuse permissions

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