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The eye lens has evolved to retain transparency throughout the organismal lifespan in the absence of cellular regeneration. The crystallin proteins that constitute the lens remain folded and soluble for more than 50 years in humans despite daily exposure to ultraviolet (UV) radiation. Human γD-crystallin (HGD) is one of the principal structural proteins of the lens. Long regarded as a passive structural protein, growing evidence indicates that HGD participates actively in light-driven redox chemistry. HGD provides a unique system for investigating the molecular mechanisms that protect long-lived proteins from photodamage (1). Oxidative ageing drives the formation of intramolecular disulfide bonds and glutathionylated cysteine residues through sulfur-centred chemistry. We hypothesise that these transient modifications enhance quenching of excited tryptophan residues to suppress further photooxidation, limiting the formation of intermolecular disulfide bonds that ultimately promote protein aggregation and cataract formation (2).
This work combines time-resolved X-ray crystallography with complementary X-ray spectroscopic techniques (3) to investigate sulfur photochemistry across timescales ranging from femtoseconds to milliseconds. XFEL measurements have established a mechanistic framework for understanding how HGD mitigates oxidative stress through controlled redox transitions. Capturing transient sulfur-centred intermediates, these experiments allow structural changes to be correlated with the spectroscopic signatures of evolving electronic states. Complementary femtosecond X-ray absorption spectroscopy enables us to identify the timescales and chemical identities of sulfur radical and ionic species formed during disulfide photochemistry, providing direct insight into the earliest events following photoexcitation. Together, these approaches define light-induced redox pathways by linking ultrafast electronic processes with protein structural dynamics. This integrated view of sulfur photochemistry provides new insight into the molecular mechanisms of photoinduced oxidative ageing in the lens and eventual cataract formation.
(1) Schafheimer, N. and King, J. (2013), Tryptophan Cluster Protects Human γD-Crystallin from Ultraviolet Radiation-Induced Photoaggregation In Vitro. Photochem Photobiol, 89, 1106-1115.
(2) Hill, J.A., Nyathi, Y., Horrell, S., von Stetten, D., Axford, D., Owen, R.L., Beddard, G.S., Pearson, A.R., Ginn, H.M. and Yorke, B.A. (2024), An ultraviolet-driven rescue pathway for oxidative stress to eye lens protein human gamma-D crystallin. Communications Chemistry, 7(1), p.81.
(3) Ochmann, M., Harich, J., Ma, R., Freibert, A., Kim, Y., Gopannagari, M., Hong, D.H., Nam, D., Kim, S., Kim, M., Eom, I., Lee, J.K., Yorke, B.A., Kim, T.K. and Huse, N. (2024). UV photochemistry of the L-cystine disulfide bridge in aqueous solution investigated by femtosecond X-ray absorption spectroscopy. Nature Communications, 15(1), p.8838.
| Scientific Topics | Biology |
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