Project description
Understanding structure–function relationships of bistable rhodopsins
Bistable rhodopsins are naturally photosensitive G-protein coupled receptors (GPCRs) responsible for photosensitivity and vision in animals. Bistable rhodopsins are also a potential source of strong optogenetic tools allowing bidirectional control of influential intracellular signalling cascades in all light-using body systems. However, knowledge of their biology and their engineering for optogenetic scopes is restricted due to limited understanding of their structure–function relationships. The EU-funded SOL project will investigate how structural characteristics of these influential photoreceptors determine their bistability, bichromicity, kinetics and G-protein selectivity. The project will apply this knowledge for rational engineering towards colour tuning and G-protein selectivity for optogenetic tools and investigate physiological functions. SOL will produce pioneering optogenetic techniques allowing for definition of GPCR signalling activities.
Objective
Bistable rhodopsins are naturally photosensitive G-protein coupled receptors (GPCRs) that can be toggled between stable ON and OFF states using light. They are responsible for photosensitivity and vision across animals (including humans), and a potential source of powerful optogenetic tools enabling bidirectional control of influential intracellular signalling cascades across all body systems using light. Lack of understanding of structure-function relationships for these proteins curtails understanding of their biology and their engineering for optogenetic purposes.
PI Kleinlogel first demonstrated that chimeras between bistable rhodopsin and ligand GPRCs can be functionally active and provoke a strong physiological response when expressed in vivo. PI Schertler has extensive experience in the structural analysis of rhodopsins and has successfully solved the first structure of a recombinantly expressed bistable rhodopsin. PI Hegemann has longstanding experience in the spectroscopic characterisation and engineering of photoreceptor proteins and is one of the founding fathers of optogenetics. PI Lucas pioneered cellular systems suitable for analysing spectral properties and G protein selectivity and had a leading role in elucidating the physiological role of the bistable rhodopsin melanopsin.
Together, the team aims to understand how structural features of these influential photoreceptors define their bistability, bichromicity, kinetics, and G-protein selectivity (Objective 1). We will exploit this knowledge for rational engineering towards colour tuning and G protein selectivity for optogenetic tools (Objective 2) and to probe physiological functions (Objective 3). The result will be a decisive step towards a general theory of structure-function relationship in photoreceptors and will produce a new generation of powerful optogenetic tools enabling defined GPCR signalling activities in any cell type.
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Funding Scheme
ERC-SyG - Synergy grantHost institution
5232 Villigen Psi
Switzerland