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Abstract
GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) family. Mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Using the N-terminal fragment of GPR56 (GPR56N) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56N, the ligand binding domain. This domain contains four disease-associated mutations and two N-glycosylation sites. Our study reveals that although glycosylation is not required for ligand binding, each of the four disease-associated mutations completely abolish the ligand binding ability of GPR56. Our data indicates that these four single missense mutations cause BFPP mostly by abolishing the ability of GPR56 to bind to its ligand, collagen III, in addition to affecting GPR56 protein surface expression as previously shown.
Highlights
Adhesion G protein-coupled receptor (GPCR) are a relatively new family of GPCRs that have a very long N-terminal extracellular domain
Deletion of Gpr56 has no effect on the expression of collagen III protein and GPR56N binding patterns (Fig. 1C and F), whereas loss of Col3a1 completely removed the binding of GPR56N (Fig. 1E)
GPR56 is a distinct member of the adhesion GPCRs since its mutations are associated with a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP) [3,9,10]
Summary
Adhesion GPCRs are a relatively new family of GPCRs that have a very long N-terminal extracellular domain. There are a total of 33 members of adhesion GPCRs that are thought to mediate cell-cell and cell-extracellular matrix interaction, with GPR56 as the first one linked to a human developmental malformation [1,2]. Mutations in GPR56 cause BFPP, a specific human brain malformation [3,4]. A total of fourteen BFPP-associated mutations have been identified, including one deletion, two splicing, and eleven missense mutations [2,5]. We can only say for certain that the two mutations in the GPCR proteolytic site (GPS) domain, C346S and W349S, cause a brain malformation through trapping the mutated proteins in the endoplasmic reticulum [6]
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