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  • Title: Formation of a powerful capping motif corresponding to start of "helix 12" in agonist-bound estrogen receptor-alpha contributes to increased constitutive activity of the protein.
    Author: Skafar DF.
    Journal: Cell Biochem Biophys; 2000; 33(1):53-62. PubMed ID: 11322512.
    Abstract:
    The human estrogen receptor alpha (hERalpha), a ligand-activated transcription factor, provides an excellent system for study of the conversion of a protein from inactive to active states. It binds to many different ligands which leads which to the expression or the suppression of genes in a cell-specific and promoter-specific manner, and a multitude of mutations have been identified that modify the activity of the receptor. Helix 12 is a key alpha-helix in the hormone-binding domain of the hERalpha that is directly involved in transcription activation. In this report, tyrosine 537 has been identified as the Ncap residue of helix 12 in the structures of the agonist-bound hERalpha ligand-binding domain. A capping motif has been identified in the sequence of the hERalpha that corresponds to the start of helix 12 in the fully active, agonist-bound conformation of the receptor. Analysis of the literature indicates that, with one exception, substitution of amino acids at position 537, which occur more frequently at the Ncap than tyrosine, is correlated with increased constitutive activity of the hERalpha. The results are consistent with the hypothesis that formation of a powerful capping motif that corresponds to the start of helix 12 in the agonist-bound receptor contributes to activation of the hERalpha. This is the first proposed example in which mutations that alter helix capping would lead to the constitutive activation of a protein. This hypothesis could therefore provide a novel mechanism through which mutations play a role in pathological processes.
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