แนวคิดหลัก
The calcium-sensing receptor (CaSR) can activate multiple G-protein subtypes through a common binding mode, facilitated by the receptor's dimeric structure and the flexibility of its intracellular loops.
บทคัดย่อ
The content discusses the structural basis for the calcium-sensing receptor's (CaSR) ability to signal through various G-protein subtypes, including Gq, Gi, and Gs. Key insights:
The homodimeric CaSR couples to a single G protein through a common binding mode, where the C-terminal helix of each Gα subunit binds to a shallow pocket formed by the receptor's intracellular loops, transmembrane helix 3, and C-terminal region.
G-protein binding expands the transmembrane dimer interface, which is further stabilized by phospholipid. The restraint imposed by the receptor dimer, combined with the flexibility of intracellular loop 2 (ICL2), enables G-protein activation by facilitating the conformational transition of Gα.
A single Gα residue determines the selectivity between Gq/Gs and Gi subtypes, while the length and flexibility of ICL2 allow CaSR to bind all three Gα subtypes, conferring the capacity for promiscuous G-protein coupling.
The functional pleiotropy of CaSR, which mediates diverse cellular processes beyond calcium homeostasis, is attributed to its ability to signal through multiple G-protein pathways.
สถิติ
The calcium-sensing receptor (CaSR) can detect fluctuations in extracellular Ca2+ concentration and maintain Ca2+ homeostasis.
CaSR can signal through several G-protein subtypes, including Gq, Gi, and Gs.
The CaSR-G-protein complexes studied involve a single G protein binding to the homodimeric CaSR.
G-protein binding expands the transmembrane dimer interface of CaSR, which is further stabilized by phospholipid.
A single Gα residue determines the selectivity between Gq/Gs and Gi subtypes.
คำพูด
"The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes."
"We found that the homodimeric CaSR of each complex couples to a single G protein through a common mode."
"The restraint imposed by the receptor dimer, in combination with ICL2, enables G-protein activation by facilitating conformational transition of Gα."