A disease-associated mutation in the adhesion GPCR BAI2 (ADGRB2) increases receptor signaling activity

• Type of Material: Article
• Authors: Ryan H. Purcell, Emory University; Camilo Toro, National Institute of Health; William A. Gahl, National Institute of Health; Randy Hall, Emory University
• Language: English
• Date: 2017-12-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Wiley Periodicals, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1002/humu.23336
• Title of Journal or Parent Work: Human Mutation
• ISSN: 1059-7794
• Volume: 38
• Issue: 12
• Start Page: 1751
• End Page: 1760
• Grant/Funding Information: This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, Office of the Director, National Institutes of Health (NIH). Additional funding provided by NIH NINDS R21 NS094136
• Keywords: Science & Technology; G beta gamma; Gz; ANTAGONIST; DNA-SEQUENCING DATA; RGS20; SITE; ALPHA-LATROTOXIN; BETA-GAMMA-SUBUNITS; PROTEIN-COUPLED RECEPTORS; brain; ACTIVATION; activation; FRAMEWORK; NFAT; Genetics & Heredity; Life Sciences & Biomedicine; INHIBITOR; INTERACTS
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

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 Gαz, with the R1465W mutation conferring increased coupling to Gαi. The R1465W mutation also increases the total and surface expression of BAI2. The mutation has no effect on receptor binding to β-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.