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Finding novel intragenic suppressors of a constitutively active allele of Gs alpha
Author(s) -
Janevska Daniela,
Din Eraj,
Tobar-Rubin Raquel,
Alvarez Rebecca,
Chaudhry Faiza
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.666.1
Subject(s) - allele , mutant , gene , suppressor , genetics , effector , protein subunit , biology , mutation , gtp' , yeast , microbiology and biotechnology , enzyme , biochemistry
McCune‐Albright Syndrome (MAS) is a genetic disorder caused by mutations that inhibit GTP hydrolysis in Gsα, permanently activating the protein. We have developed a yeast model system for MAS in which mutations in the yeast Gα subunit homologous to those seen in MAS (R297H) prevent colony formation when the mutant allele is the only Gα gene present in the cells. We then constructed of a library of 32,000 secondary mutations in the constitutively active yeast Gα gene with the goal of identifying intragenic suppressors of the MAS mutation. Nine novel suppressor alleles have been identified and have been mapped to the crystal structure of the Gsαƒnprotein. Suppressor mutations have been identified in the GTP‐binding site of the protein, near the βγ‐interaction surface, on a potential effector interaction surface, in switch III, and also on regions of the α subunit with no currently characterized function. The construction of a detailed map of sites on the surface of Gα which can inactivate the MAS allele can drive rational drug discovery of better treatments for MAS patients. Funded by NIH grant 1R15ED020190‐01