Gain-of-function mutations in heterotrimeric G-protein α subunits are associated with a variety of human diseases. McCune-Albright syndrome (MAS) is caused by mutations in GNAS, the gene encoding Gs. Alterations at Arg201 significantly reduce the GTPase activity of the protein, rendering it constitutively active. In this study, we have constructed a library of random mutations in a constitutively active yeast GPA1 gene carrying a mutation homologous to the McCune-Albright allele (Arg297His). Intragenic suppressors found at sites with homology to the human Gs protein were tested for their ability to suppress the constitutive activity of an Arg201His mutation in Gs. Three intragenic suppressors, at Phe142, Arg231, and Leu266, were able to suppress elevated basal cAMP responses caused by Arg201His when expressed in HEK293 cells. A range of amino acid substitutions was introduced at each of these sites to investigate the chemical requirements for intragenic suppression. The ability of Gs proteins carrying the suppressor mutations alone to mediate receptor-induced cAMP production was measured. These results offer potential sites on Gs that could serve as drug targets for MAS therapies.
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Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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Site | Modification | Modifier | Source | Reference |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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