Document Detail


Intragenic suppression of a constitutively active allele of Gsα associated with McCune-Albright syndrome.
MedLine Citation:
PMID:  23288949     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
McCune-Albright syndrome (MAS) is a human genetic disorder caused by a mutation that constitutively activates the G(s)α subunit by abolishing GTP hydrolysis. MAS patients suffer from a range of endocrinopathies as well as polyostotic fibrous dysplasia of bone. We previously identified an intragenic suppressor of the MAS mutation in a yeast system, which substituted two residues in the GTP-binding site of Gpa1: L318P and D319V to suppress the constitutive activity of an R297H mutation, corresponding to the human F222P, D223V, and R201H mutations respectively. To extend these studies, the human GNAS gene was subjected to site-directed mutagenesis. Constructs expressing the MAS mutation (R201H), the MAS mutation plus the mutations homologous to the yeast suppressors (R201H, F222P/D223V), or the yeast suppressor mutation alone (F222P/D223V) were transfected into HEK293 cells, and basal and receptor-stimulated cAMP levels were measured. Expression of R201H increased the basal cAMP levels and decreased the EC(50) for hormone-stimulated cAMP production. These effects were dependent on the amount of R201H protein expressed. R201H, F222P/D223V abolished the constitutive activity of the MAS mutation and caused responses to hormone that were not different from those measured in cells expressing WT G(s)α. Interestingly, F222P/D223V behaved similar to R201H in causing increases in basal cAMP production, thus demonstrating constitutive activity. Substitution of another acidic (E) or polar (N, T, and G) amino acid at position 223 caused no suppression of R201H activity, while substitution of a second nonpolar amino acid (A) at this position partially suppressed, and the larger polar I residue completely suppressed the effects of R201H.
Authors:
Raquel Tobar-Rubin; Dahlia Sultan; Daniela Janevska; Kyle Turcic; Julie Carroll; Laura Ooms; Robin Pals-Rylaarsdam
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-26
Journal Detail:
Title:  Journal of molecular endocrinology     Volume:  50     ISSN:  1479-6813     ISO Abbreviation:  J. Mol. Endocrinol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-02-27     Completed Date:  2013-08-08     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  8902617     Medline TA:  J Mol Endocrinol     Country:  England    
Other Details:
Languages:  eng     Pagination:  193-201     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Alleles*
Amino Acid Sequence
Binding Sites
Cell Line
Cyclic AMP
Fibrous Dysplasia, Polyostotic / genetics*
GTP-Binding Protein alpha Subunits, Gs / chemistry,  genetics*
Gene Expression Regulation
Humans
Models, Molecular
Molecular Sequence Data
Protein Binding
Protein Conformation
Sequence Alignment
Suppression, Genetic*
Grant Support
ID/Acronym/Agency:
1R15DE020190-01/DE/NIDCR NIH HHS; 3R15DE020190-01S1/DE/NIDCR NIH HHS; R15 DE020190/DE/NIDCR NIH HHS
Chemical
Reg. No./Substance:
E0399OZS9N/Cyclic AMP; EC 3.6.5.1/GTP-Binding Protein alpha Subunits, Gs
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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