Journal
HUMAN MUTATION
Volume 38, Issue 12, Pages 1751-1760Publisher
WILEY
DOI: 10.1002/humu.23336
Keywords
activation; brain; Gz; G beta gamma; NFAT; RGS20
Categories
Funding
- Intramural Research Program of the National Human Genome Research Institute
- Common Fund, Office of the Director, National Institutes of Health (NIH)
- NIH National Institute of Neurological Disorders and Stroke [R21 NS094136]
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Mutations in G protein-coupled receptors (GPCRs) that increase constitutive signaling activity can cause human disease. A de novo C-terminal mutation (R1465W) in the adhesion GPCR BAI2 (also known as ADGRB2) was identified in a patient suffering from progressive spastic paraparesis and other neurological symptoms. In vitro studies revealed that this mutation strongly increases the constitutive signaling activity of an N-terminally cleaved form of BAI2, which represents the activated form of the receptor. Further studies dissecting the mechanism(s) underling this effect revealed that wild-type BAI2 primarily couples to alpha G(z), with the R1465W mutation conferring increased coupling to G alpha(i). The R1465W mutation also increases the total and surface expression of BAI2. The mutation has no effect on receptor binding to beta-arrestins, but does perturb binding to the endocytic protein endophilin A1, identified here as a novel interacting partner for BAI2. These studies provide new insights into the signaling capabilities of the adhesion GPCR BAI2/ADGRB2 and shed light on how an apparent gain-of-function mutation to the receptor's C-terminus may lead to human disease.
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