How do receptors multi-task across different organs and tissues in the body?
The international team which includes Professor Arthur Conigrave from the University of Sydney explains how the calcium-sensing receptor and other related receptors can multi-task. The calcium-sensing receptor (CaSR) is critical for bodily calcium metabolism and for bone health. It is also a member of the superfamily of G protein-coupled receptors (GPCRs), which contains over 700 members.
International collaboration
When Professor Qing Fan, Professor of Molecular Pharmacology and Therapeutics and Pathology and Cell Biology, Columbia University, first teamed-up with Professor Emeritus Arthur Conigrave, a cell and molecular biologist from the University of Sydney, in 2015 it was known that the CaSR had roles in calcium homeostasis (keeping the calcium level in the blood constant), protein nutrition (detecting and responding to the constituent amino acids released upon digestion of dietary protein), and even in changing cell fate and cell number in normal and cancerous cell types.
However, the underlying structural features that supported these very different functions – allowing the CaSR to multitask – were unknown.
Professor Arthur Conigrave and Professor Quing R Fan
In joining the collaborative partnership, Professor Conigrave used his expertise to help select optimal biochemical conditions for the results of tissue-specific receptor function to identify G protein partners of interest.
Nine years on, and with articles in eLife, PNAS, and now Nature, the evolving story has identified the sites of calcium, amino acid and modulator drug binding, identified a new inhibitory binding site for phosphate (the mineral partner of calcium in bone), described the coordinated receptor protein motions above, within, and below the membrane, and now explained how the receptor’s effector G proteins dock like a dormant robotic pod to the mothership and are activated.
Targeting cancer-specific CaSR-induced Gs activation might also be feasible, particularly when cancer cells come into contact with bone
These G protein ‘pods’ are managed differently in different tissues of the body according to subtype.
In the new work, the team used cryo-electron microscopy to visualise CaSR coupling to different G proteins. The images helped the team identify structural elements in both the CaSR and in the distinct G proteins that determine docking and activation. The team found that a particular loop is critical for multitasking and the length and flexibility of this loop allows docking and activation of all key G protein subtypes.
What this research means
"These discoveries will assist the design of therapeutics that target specific CaSR signaling pathways," said Professor Fan.
‘Targeting cancer-specific CaSR-induced Gs activation might also be feasible, particularly when cancer cells come into contact with bone," said Professor Conigrave.
"But then there is also a whole new frontier of protein nutrition to work on."
The most recent research was supported by the Department of Energy Office of Biological and Environmental Research (KP1607011), the National Institutes of Health (U24GM129539 and R35GM141871), the Simons Foundation (SF349247), the New York State Assembly and the Hope for Depression Research Foundation. Professor Conigrave acknowledges support from NHMRC (APP1085143 and APP1138891).