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

Roskamp, K. W., Azim, S., Kassier, G., Norton-Baker, B., Sprague-Piercy, M. A., Miller, R. J. D., et al. (2020). Human γS-Crystallin–Copper Binding Helps Buffer against Aggregation Caused by Oxidative Damage. Biochemistry, 59(25), 2371-2385. doi:10.1021/acs.biochem.0c00293.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-A0A8-7 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-C65B-5
Genre: Journal Article

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Supporting information: 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
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https://dx.doi.org/10.1021/acs.biochem.0c00293 (Publisher version)
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 Creators:
Roskamp, K. W.1, Author
Azim, S.2, 3, 4, Author              
Kassier, G.3, 4, Author
Norton-Baker, B.1, 3, 4, Author
Sprague-Piercy, M. A.5, Author
Miller, R. J. D.3, 4, 6, Author
Martin, R. W.1, 5, Author
Affiliations:
1Department of Chemistry, University of California, ou_persistent22              
2International Max Planck Research School for Ultrafast Imaging & Structural Dynamics (IMPRS-UFAST), Max Planck Institute for the Structure and Dynamics of Matter, Max Planck Society, ou_2266714              
3Miller Group, Atomically Resolved Dynamics Department, Max Planck Institute for the Structure and Dynamics of Matter, Max Planck Society, ou_persistent22              
4Center for Free Electron Laser Science, ou_persistent22              
5Department of Molecular Biology and Biochemistry, University of California, ou_persistent22              
6Departments of Chemistry and Physics, University of Toronto, ou_persistent22              

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 Abstract: 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, UV light damage, and the addition of metal ions. All three aggregation pathways result in globular, amorphous 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 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.

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Language(s): eng - English
 Dates: 2020-06-072020-04-102020-06-082020-06-30
 Publication Status: Published in print
 Pages: 15
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1021/acs.biochem.0c00293
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Title: Biochemistry
Source Genre: Journal
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Publ. Info: Columbus, Ohio : American Chemical Society
Pages: - Volume / Issue: 59 (25) Sequence Number: - Start / End Page: 2371 - 2385 Identifier: ISSN: 0006-2960
CoNE: https://pure.mpg.de/cone/journals/resource/954925384103