Androgen receptor mutations causing human androgen insensitivity syndromes show a key role of residue M807 in helix 8-helix 10 interactions and in receptor ligand-binding domain stability

Y. C. Ong, Prasanna Kolatkar, E. L. Yong

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Abstract

Transactivation activity of the androgen receptor (AR) is induced by the binding of an androgen to its ligand-binding domain (LBD). The tertiary architecture of the AR LBD, in common with other steroid/nuclear receptors, is a sandwich of 12 α-helices (H). We have encountered a missense substitution, M807T, which was associated with partially defective androgen binding in a 46,XY infant with ambiguous genitalia. In contrast, two other substitutions in the same residue 807 to valine and arginine, resulted in almost total abrogation of androgen-binding and complete androgen insensitivity syndrome in two unrelated individuals. We recreated these substitutions in residue 807 and observed that disruption of ligand-binding and transactivation activities was total for M807R and partial for M807V, while the least-affected was M807T. Modelling of the AR LBD indicate that van der Waal interactions between residue 807 (H8) to H9 and H10 were severely disrupted for the arginine mutant, but relatively preserved for the threonine and valine mutants. However, there was a subtle difference between these two variants in that M807T, but not M807V, improved van der Waal contacts with another residue L859 in H10, suggesting the importance of interactions between M807 and L859 for LBD stability. Atomic distances of M807 (H8) to L859 (H10) in corresponding residues of the distantly related ERα, RXRα, PPARγ and VDR LBD are highly conserved and almost invariant, suggesting that H8/H10 interactions are critical for LBD stability in other members of the steroid/nuclear receptor superfamily.

Original languageEnglish
Pages (from-to)101-108
Number of pages8
JournalMolecular Human Reproduction
Volume8
Issue number2
Publication statusPublished - 26 Feb 2002
Externally publishedYes

Fingerprint

Androgen-Insensitivity Syndrome
Androgen Receptors
Ligands
Mutation
Androgens
Steroid Receptors
Valine
Cytoplasmic and Nuclear Receptors
Transcriptional Activation
Arginine
Disorders of Sex Development
Peroxisome Proliferator-Activated Receptors
Threonine

Keywords

  • Androgen receptor
  • Helical stability
  • Mutations

ASJC Scopus subject areas

  • Obstetrics and Gynaecology
  • Genetics
  • Developmental Biology
  • Embryology
  • Cell Biology

Cite this

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title = "Androgen receptor mutations causing human androgen insensitivity syndromes show a key role of residue M807 in helix 8-helix 10 interactions and in receptor ligand-binding domain stability",
abstract = "Transactivation activity of the androgen receptor (AR) is induced by the binding of an androgen to its ligand-binding domain (LBD). The tertiary architecture of the AR LBD, in common with other steroid/nuclear receptors, is a sandwich of 12 α-helices (H). We have encountered a missense substitution, M807T, which was associated with partially defective androgen binding in a 46,XY infant with ambiguous genitalia. In contrast, two other substitutions in the same residue 807 to valine and arginine, resulted in almost total abrogation of androgen-binding and complete androgen insensitivity syndrome in two unrelated individuals. We recreated these substitutions in residue 807 and observed that disruption of ligand-binding and transactivation activities was total for M807R and partial for M807V, while the least-affected was M807T. Modelling of the AR LBD indicate that van der Waal interactions between residue 807 (H8) to H9 and H10 were severely disrupted for the arginine mutant, but relatively preserved for the threonine and valine mutants. However, there was a subtle difference between these two variants in that M807T, but not M807V, improved van der Waal contacts with another residue L859 in H10, suggesting the importance of interactions between M807 and L859 for LBD stability. Atomic distances of M807 (H8) to L859 (H10) in corresponding residues of the distantly related ERα, RXRα, PPARγ and VDR LBD are highly conserved and almost invariant, suggesting that H8/H10 interactions are critical for LBD stability in other members of the steroid/nuclear receptor superfamily.",
keywords = "Androgen receptor, Helical stability, Mutations",
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T1 - Androgen receptor mutations causing human androgen insensitivity syndromes show a key role of residue M807 in helix 8-helix 10 interactions and in receptor ligand-binding domain stability

AU - Ong, Y. C.

AU - Kolatkar, Prasanna

AU - Yong, E. L.

PY - 2002/2/26

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N2 - Transactivation activity of the androgen receptor (AR) is induced by the binding of an androgen to its ligand-binding domain (LBD). The tertiary architecture of the AR LBD, in common with other steroid/nuclear receptors, is a sandwich of 12 α-helices (H). We have encountered a missense substitution, M807T, which was associated with partially defective androgen binding in a 46,XY infant with ambiguous genitalia. In contrast, two other substitutions in the same residue 807 to valine and arginine, resulted in almost total abrogation of androgen-binding and complete androgen insensitivity syndrome in two unrelated individuals. We recreated these substitutions in residue 807 and observed that disruption of ligand-binding and transactivation activities was total for M807R and partial for M807V, while the least-affected was M807T. Modelling of the AR LBD indicate that van der Waal interactions between residue 807 (H8) to H9 and H10 were severely disrupted for the arginine mutant, but relatively preserved for the threonine and valine mutants. However, there was a subtle difference between these two variants in that M807T, but not M807V, improved van der Waal contacts with another residue L859 in H10, suggesting the importance of interactions between M807 and L859 for LBD stability. Atomic distances of M807 (H8) to L859 (H10) in corresponding residues of the distantly related ERα, RXRα, PPARγ and VDR LBD are highly conserved and almost invariant, suggesting that H8/H10 interactions are critical for LBD stability in other members of the steroid/nuclear receptor superfamily.

AB - Transactivation activity of the androgen receptor (AR) is induced by the binding of an androgen to its ligand-binding domain (LBD). The tertiary architecture of the AR LBD, in common with other steroid/nuclear receptors, is a sandwich of 12 α-helices (H). We have encountered a missense substitution, M807T, which was associated with partially defective androgen binding in a 46,XY infant with ambiguous genitalia. In contrast, two other substitutions in the same residue 807 to valine and arginine, resulted in almost total abrogation of androgen-binding and complete androgen insensitivity syndrome in two unrelated individuals. We recreated these substitutions in residue 807 and observed that disruption of ligand-binding and transactivation activities was total for M807R and partial for M807V, while the least-affected was M807T. Modelling of the AR LBD indicate that van der Waal interactions between residue 807 (H8) to H9 and H10 were severely disrupted for the arginine mutant, but relatively preserved for the threonine and valine mutants. However, there was a subtle difference between these two variants in that M807T, but not M807V, improved van der Waal contacts with another residue L859 in H10, suggesting the importance of interactions between M807 and L859 for LBD stability. Atomic distances of M807 (H8) to L859 (H10) in corresponding residues of the distantly related ERα, RXRα, PPARγ and VDR LBD are highly conserved and almost invariant, suggesting that H8/H10 interactions are critical for LBD stability in other members of the steroid/nuclear receptor superfamily.

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