Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist.
作者： Hannah M. Stoveken , Alexander G. Hajduczok , Lei Xu , Gregory G. Tall
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摘要: The large class of adhesion G protein-coupled receptors (aGPCRs) bind extracellular matrix or neighboring cell-surface ligands to regulate organ and tissue development through an unknown activation mechanism. We examined aGPCR using two prototypical aGPCRs, GPR56 GPR110. Active dissociation the noncovalently bound GPR110 domains (ECDs) from respective seven-transmembrane (7TM) relieved inhibitory influence permitted both activate defined protein subtypes. After ECD displacement, newly revealed short N-terminal stalk regions 7TM were found be essential for activation. Synthetic peptides comprising these stalks potently activated in vitro cells, demonstrating that comprise a tethered agonist was encrypted within ECD. Establishment mechanism provides rational platform synthetic modulators could find clinical utility toward aGPCR-directed disease.
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