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J Recept Signal Transduct Res. 2015 Jun;35(3):220-3. doi: 10.3109/10799893.2015.1072978. Epub 2015 Sep 14.

Tethered agonists: a new mechanism underlying adhesion G protein-coupled receptor activation.

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a Institute of Biochemistry, Medical Faculty, University of Leipzig , Leipzig , Germany .
b Division of Newborn Medicine, Department of Medicine , Children's Hospital and Harvard Medical School , Boston , MA , USA .
c Department of Developmental Biology , Washington University School of Medicine , St. Louis , MO , USA , and.
d Hope Center for Neurological Disorders, Washington University School of Medicine , St. Louis , MO , USA.


The family of adhesion G protein-coupled receptors (aGPCRs) comprises 33 members in the human genome, which are subdivided into nine subclasses. Many aGPCRs undergo an autoproteolytic process via their GPCR Autoproteolysis-INducing (GAIN) domain during protein maturation to generate an N- and a C-terminal fragments, NTF and CTF, respectively. The NTF and CTF are non-covalently reassociated on the plasma membrane to form a single receptor unit. How aGPCRs are activated upon ligand binding remains one of the leading questions in the field of aGPCR research. Recent work from our labs and others shows that ligand binding can remove the NTF from the plasma membrane-bound CTF, exposing a tethered agonist which potently activates downstream signaling.


G protein-coupled signaling; adhesion GPCR; tethered agonist

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