Photoactivatable zinc sensors: one step closer towards understanding zinc’s role in neurodegeneration.
Annika Pick, Technische Universität Kaiserslautern
Zinc is essential for the human organism. Despite its role in protein function and the immune system, it is crucial for signal transduction. A dysregulation of zinc homeostasis and zinc related processes can lead to a number of cognitive defects and neurodegenerative diseases, e.g. Alzheimer’s and Parkinson’s disease, epilepsy or attention deficit hyperactivity disorder, – a growing issue in an aging society.[1]-[5] An understanding of the underlying molecular mechanisms could lead to the development of therapeutics, which could preserve or even improve the quality of life of many affected people. However, little is known about zinc signaling at the molecular level. Synthetic chemistry can contribute to the investigation of zinc signaling by providing tailor-made zinc-sensing tools: fluorescent zinc sensors. Lippard et al. established fluorescent zinc sensors based on fluoresceine, which consist of a zinc-binding and a reporting (fluorescent) unit, whereas the latter emits light upon zinc binding.[6] However, one of the biggest challenges has not been met, yet: the achievement of spatiotemporal resolution to perform long-term studies. To address this challenge, I seek to develop photoactivatable zinc sensors whose zinc sensing property can selectively be turned on and off via an external stimulus. For this, we identified azobenzene, a chemical photoswitch, as suitable unit to prepare photoactivatable zinc sensors. Azobenzene is inserted into the sensor backbone, thereby separating the reporting and zinc-binding unit. In the idle state, i.e. prior to photoactivation, zinc binding is inhibited due to physical separation of both units. Irradiation with light then triggers a structural change of the azobenzene backbone, which re-establishes the spatial proximity of the two units, and thus, re-constitutes a fully working zinc sensor. In a simplified picture, the sensor’s mode of operation can be compared to the motion of a person catching a thrown ball with both hands – only by bringing together both hands, catching of the ball is possible.
References:
[1] R. J. Radford, S. J. Lippard, Curr. Opin. Chem. Bio., 17, 129–136, 2013.
[2] P. Zatta, D. Drago, S. Bolognin, S. L. Sensi, Trends Pharmacol. Sci., 7, 346–355, 2009.
[3] R. W. Wojciak, E. Mojs, M. Stanislawska-Kubiak, W. Samborski, Epilepsy Res., 1–2, 40–44, 2013.
[4] S. Pfaender, A. M. Grabrucker, Metallomics, 5, 960–977, 2014.
[5] P. Paoletti, C. Bellone, Q. Zhou, Nat. Rev. Neurosci., 14, 383–400, 2013.
[6] C. C. Woodroofe, R. Masalha, K. R. Barnes, C. J. Frederickson, S. J. Lippard, Chem. Bio., 11,
1659–1666, 2004.