Bio­lo­gic­al sys­tem with light switch

The aim of opto­gen­et­ics is to con­trol genet­ic­ally mod­i­fied cells using light. A team of Graz sci­ent­ists led by Andreas Wink­ler from the Insti­tute of Bio­chem­istry at TU Graz have set a mile­stone in the future devel­op­ment of nov­el red-light reg­u­lated opto­gen­et­ic tools for tar­geted cell stim­u­la­tion. For the first time ever, they were able to observe molecu­lar prin­ciples of sensor-effect­or coup­ling in the full-length struc­ture of a red-light respons­ive pro­tein and describe detailed mech­an­isms of sig­nal trans­mis­sion over long dis­tances at a molecu­lar level.

Helix as light switch

To sur­vive, cells and organ­isms have to adapt to new envir­on­ment­al con­di­tions. This is the job of ​“pro­tein build­ing blocks” which inter­act with each oth­er in dif­fer­ent ways, thus cre­at­ing cel­lu­lar net­works which allow adapt­a­tions to be made to changed envir­on­ments. The sensors or ​“recept­ors” of extern­al stim­u­la­tion, such as light, are at least in part coupled to spe­cif­ic effect­ors in order to spe­cific­ally activ­ate or inhib­it cel­lu­lar sig­nal molecules depend­ing on need. The Graz research group, which com­prises not only research­ers from TU Graz but also sci­ent­ists from the Med­ic­al Uni­ver­sity of Graz, presents molecu­lar details of a red-light photo-recept­or, involved in the pro­duc­tion of a cent­ral bac­teri­al mes­sen­ger molecule, and describes the struc­ture of a full-length light-recept­or togeth­er with its enzymat­ic effect­or for the first time. The archi­tec­ture and com­pos­i­tion of the linker ele­ment con­nect­ing the sensor and effect­or is very import­ant in light reg­u­la­tion. TU Graz bio­chem­ist Andreas Wink­ler, head of the research group: ​“By using a com­bin­a­tion of x‑ray struc­tur­al ana­lys­is and hydro­gen-deu­teri­um exchange, by which the struc­tur­al dynam­ics and con­form­a­tion­al changes can be ana­lysed, we man­aged to bet­ter under­stand the func­tion­al char­ac­ter­ist­ics of this hel­ic­al coup­ling ele­ment. We were able to show that illu­min­at­ing the sensor with red light res­ul­ted in a rota­tion-like change in the coiled coil linker region, which in turn effects the enzymat­ic activ­ity of the neigh­bour­ing effect­or.” The Graz research­ers were thus able to determ­ine struc­tur­al details of a red-light reg­u­lated full-length sys­tem and describe molecu­lar mech­an­isms of sig­nal trans­duc­tion.

Towards a ration­al design of proteins

The research con­trib­utes to bet­ter under­stand­ing the mod­u­lar­ity of nat­ur­ally occur­ring pro­tein domains and being able to devel­op new opto­gen­et­ic tools. Diverse com­bin­a­tions of dif­fer­ent sensor mod­ules are found in nature, such as red-light sensors, blue-light sensors and pH sensors – some­times with identic­al and some­times dif­fer­ent effect­ors. From this, the research­ers con­clude that there are molecu­lar sim­il­ar­it­ies in sig­nal trans­duc­tion and there­fore that ration­al and com­pletely arbit­rary com­bin­a­tions of sensors and effect­ors which do not occur in nature are con­ceiv­able. Andreas Wink­ler: ​“We are cur­rently lim­ited to nat­ur­ally occur­ring sys­tems to a great extent in the use of dir­ectly reg­u­lated enzymat­ic func­tion­al­it­ies. The long-term aim is to gen­er­ate new light-reg­u­lated sys­tems which can over­come the lim­it­a­tions of nature and which would be of great interest for dif­fer­ent applic­a­tions in opto­gen­et­ics.” [abridged] Source: idw/​Technische Uni­versität Graz