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

Biochemistry
Kyle W RoskampRachel W Martin

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, 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 f...Continue Reading

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Citations

Jul 23, 2020·Protein Science : a Publication of the Protein Society·Calvin J VetterKirsten J Lampi
Feb 12, 2021·Chembiochem : a European Journal of Chemical Biology·Megan A RochaRachel W Martin
Jun 3, 2021·Acta Crystallographica. Section D, Structural Biology·Brenna Norton-BakerEike C Schulz
Jun 25, 2021·Analytical Chemistry·Zhan GaoYuanjiang Pan
Aug 2, 2021·Experimental Eye Research·Eugene SerebryanyLiliana Quintanar
Aug 15, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·May T MaungTeresita Padilla-Benavides
Jan 14, 2022·The Journal of Physical Chemistry. B·Brenna Norton-BakerRachel W Martin

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