The findings illuminate how signals from photons (particles of light) get amplified in the eye. More importantly, the study provides insights into how the largest family of cell membrane proteins – G-protein-coupled receptors (GPCRs) – work in humans.
“They’re involved in almost all the biological processes in a human body — how we perceive light, taste, smell, or how the heart rate is regulated or muscles contract — and they are targets for over 30% of the drugs that are used today,” said Yang Gao, co-first author of the paper and a postdoctoral researcher in the lab of Richard Cerione, the Goldwin Smith Professor of Chemistry and Chemical Biology and co-senior author.
There are over 800 GPCRs in humans that signal through about 20 different G proteins. GPCRs are responsible for sensing a wide range of outside signals — such as hormones, light, and sense of smell and taste — and inducing corresponding responses inside the cell. In vertebrate vision, the GPCR rhodopsin is capable of detecting the signal from just one photon and through the activation of the G protein transducin and downstream effectors, amplify it 100,000 times.
The researchers used cryo-electron microscopy to obtain atomic-resolution structures of the rhodopsin-transducin complex. The structures not only provide the molecular basis of vertebrate vision, but also reveal a previously unknown mechanism of how GPCRs in general activate G proteins.
“What we’ve learnt from these structures at an atomic level may be broadly applicable to other GPCR signaling systems,” said co-first author Sekar Ramachandran, a senior research associate in Cerione’s lab.
By learning more about how different receptors specifically couple with different G proteins, the researchers hope to gain insights into designing drugs that specifically regulate GPCR signaling. A lot of drug side effects occur when therapies are not specific enough and target both harmful and beneficial pathways, Yang said.
Hongli Hu, a postdoctoral researcher in Stanford’s Department of Structural Biology, is a co-first author; Georgios Skiniotis, professor of molecular and cellular physiology and of structural biology at Stanford, is a co-senior author.
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Materials provided by Cornell University.
Original written by Krishna Ramanujan.
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