Substitutions of tyrosine 601 in the human thyrotropin receptor result in increase or loss of basal activation of the cyclic adenosine monophosphate pathway and disrupt coupling to Gq/11.

Details

Serval ID
serval:BIB_BBC613AE2AAC
Type
Article: article from journal or magazin.
Collection
Publications
Title
Substitutions of tyrosine 601 in the human thyrotropin receptor result in increase or loss of basal activation of the cyclic adenosine monophosphate pathway and disrupt coupling to Gq/11.
Journal
Thyroid
Author(s)
Arseven O.K., Wilkes W.P., Jameson J.L., Kopp P.
ISSN
1050-7256 (Print)
ISSN-L
1050-7256
Publication state
Published
Issued date
01/2000
Peer-reviewed
Oui
Volume
10
Number
1
Pages
3-10
Language
english
Notes
Publication types: Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Constitutively activating mutations of the thyrotropin (TSH) receptor have been identified as a molecular cause of toxic adenomas, nonautoimmune familial hyperthyroidism, and sporadic congenital hyperthyroidism. By analyzing genomic DNA from a toxic adenoma, we detected a novel somatic mutation in codon 601, tyrosine to asparagine (Y601N), a residue located in the carboxyterminal part of the fifth transmembrane helix. This codon is also notable for the presence of a polymorphic variant, Y601H. These two naturally occurring substitutions (Y601N and Y601H) were analyzed together with an artificial mutation, Y601F, to study the role of this residue for receptor function further. Transient transfection assays revealed that the Y601N mutation results in constitutive activation of the cyclic adenosine monophosphate (cAMP) pathway, but that it is unable to couple to Gq/11. Y601H and Y601F do not display basal activity while retaining responsiveness to TSH, but also lose the ability to induce inositol phosphate accumulation in response to TSH. These studies define Y601N as a mutation that selectively activates the cAMP pathway, and they confirm that Y601H is not a silent polymorphism. In conclusion, residue Y601 has an important role for the characteristic constitutive basal activity of the TSH receptor and coupling to Gq/11.
Keywords
Adult, Amino Acid Sequence/genetics, Amino Acid Substitution/genetics, Cyclic AMP/metabolism, Female, GTP-Binding Proteins/metabolism, Humans, Molecular Sequence Data, Mutation/genetics, Mutation/physiology, Receptors, Thyrotropin/genetics, Thyrotropin/metabolism
Pubmed
Web of science
Create date
30/12/2020 15:12
Last modification date
31/12/2020 6:26
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