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Pathophysiology of Androgen Insensitivity Syndromes: Molecular and Structural Approaches of Natural and Engineered Androgen Receptor Mutations at Amino Acid 743

Institut National de la Santé et de la Recherche Médicale (INSERM) U-439, Pathologie Moléculaire des Récepteurs Nucléaires et Service d’Hormonologie, Centre Hospitalier Universitaire (CHU) de Montpellier (N.P., S.L., B.T., J.-M.A.L., C.S.); Centre de Biochimie Structurale, INSERM U-554 and Centre National de la Recherche Scientifique U-5048, Montpellier (N.P., W.B.); and Unité d’Endocriologic Pédiatrique, CHU (C.S.), 34295 Montpellier, France

Address all correspondence and requests for reprints to: Prof. Charles Sultan, INSERM, U-439, 70 rue de Navacelles, 34090 Montpellier, France. E-mail: chsultan{at}montp.inserm.fr.

Abstract

To decipher the clues of genotype-phenotype mapping in androgen insensitivity syndromes (AIS), we integrated clinical, molecular, and structural data in an investigation into the characteristics of androgen receptor (AR) ligand binding and activation. We looked for residues substituted in AIS that are conserved among the different AR species but that diverge in the other steroid receptors, thus suggesting a role in androgen binding specificity. Of the residues fitting these characteristics, we focused on the glycine at position 743, for which natural substitutions (glutamic acid and valine) have been associated with different androgen resistance phenotypes. The consequences of both substitutions were evaluated along with the minimal glycine to alanine mutation. The gradual impairment of binding and trans-activation efficiencies in AR mutants ranging from alanine to valine and subsequently glutamic acid were highlighted by in vitro experiments. Structural analyses showed the consequences of these substitutions at the atomic level and suggested a difference in local organization among the nuclear receptor superfamily. Overall, this integrative approach provides a useful tool for further investigations into the AR structure-function relationship in AIS.

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