Neofunctionalization of Androgen Receptor by Gain-of-Function Mutations in Teleost Fish Lineage.
Steroid hormone receptor family provides an example of evolution of diverse transcription factors through whole-genome duplication (WGD). However, little is known about how their functions have been evolved after the duplication. Teleosts present a good model to investigate an accurate evolutionary history of protein function after WGD, because a teleost-specific WGD (TSGD) resulted in a variety of duplicated genes in modern fishes. This study focused on the evolution of androgen receptor (AR) gene, as two distinct paralogs, ARα and ARβ, have evolved in teleost lineage after TSGD. ARα showed a unique intracellular localization with a higher transactivation response than that of ARβ. Using site-directed mutagenesis and computational prediction of protein-ligand interactions, we identified two key substitutions generating a new functionality of euteleost ARα. The substitution in the hinge region contributes to the unique intracellular localization of ARα. The substitution on helices 10/11 in the ligand-binding domain possibly modulates hydrogen bonds that stabilize the receptor-ligand complex leading to the higher transactivation response of ARα. These substitutions were conserved in Acanthomorpha (spiny-rayed fish) ARαs, but not in an earlier branching lineage among teleosts, Japanese eel. Insertion of these substitutions into ARs from Japanese eel recapitulates the evolutionary novelty of euteleost ARα. These findings together indicate that the substitutions generating a new functionality of teleost ARα were fixed in teleost genome after the divergence of the Elopomorpha lineage. Our findings provide a molecular explanation for an adaptation process leading to generation of the hyperactive AR subtype after TSGD.
Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan.
Yukiko
Y
Ogino
Phyloinformatics Unit, RIKEN Center for Life Science Technologies, Kobe, Japan.
Shigehiro
S
Kuraku
Department of Life Environmental Conservation, Faculty of Agriculture, Ehime University, Matsuyama, Japan.
Hiroshi
H
Ishibashi
Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan Center for Bioscience Research and Education, Utsunomiya University, Utsunomiya, Japan.
Hitoshi
H
Miyakawa
Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan.
Eri
E
Sumiya
Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan.
Shinichi
S
Miyagawa
Department of Aquatic Biology, Faculty of Bioindustry, Tokyo University of Agriculture, Abashiri, Japan.
Hajime
H
Matsubara
Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.
Gen
G
Yamada
Department of Medicine, University of California.
Michael E
ME
Baker
Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, and Department of Basic Biology, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan taisen@nibb.ac.jp.
Taisen
T
Iguchi
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D019143:Evolution, Molecular; D005399:Fishes / Q000235:genetics*; D020440:Gene Duplication; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics* / Q000502:physiology*; D016415:Sequence Alignment; D014157:Transcription Factors
D011944:Receptors, Androgen; D014157:Transcription Factors
androgen; evolution of protein function; genome duplication; steroid hormone receptor; teleost; transcription factor