The evolution of eukaryotic linear motifs governing the function of androgen receptor from fish to <i>Homo sapiens</i>

How essential trans-active factors that control gene expression evolved while maintaining their ability to interact with their natural effectors and cis-active elements on DNA is a fundamental question that requires multidisciplinary approaches. Focusing on a ligand-activated transcription factor (TF), namely androgen receptor (AR), we addressed how exonic eukaryotic linear motifs (ELMs), homorepeats (HReps), and amino acids subject to post-translational modifications (PTMs) evolved in 536 species from cartilaginous fish to Homo sapiens. By combining in silico (SWISS-Model and Alphafold3), computational (molecular dynamics), and biochemical and molecular approaches, we identify functionally active ELMs present in the H. sapiens AR and trace them back to Chondrichthyes, including one in the ligand-binding domain (LBD) required for androgen binding. Moreover, we provide evidence that an ELM dynamically regulated via PTM through a cryptic phosphorylation site is an old suppressive signal from fish to human. Furthermore, we identify a similar phospho-site in the LBD of the other steroid receptors and their ancestors. These findings shed light on the timing and enduring establishment of specific ELMs and their PTMs within the steroid hormone receptor (SHR) family, while highlighting early AR-specific ELMs conserved from fish to humans, as well as ELMs that emerged later in mammals.

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Publication Details

Journal
Nucleic Acids Research
Published
2025-07-19
DOI
https://doi.org/10.1093/nar/gkaf688
Citations
2
Primary Topic
Hormonal and reproductive studies
Type
article
Field-Weighted Citation Impact
2.59

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article

The evolution of eukaryotic linear motifs governing the function of androgen receptor from fish to Homo sapiens

Jessica Rosati, Antonella Falconieri, Manuela Basso, Isabella Palazzolo et al.
2 citations
Nucleic Acids Research
Hormonal and reproductive studies
2.59
article

The evolution of eukaryotic linear motifs governing the function of androgen receptor from fish to Homo sapiens

Jessica Rosati, Antonella Falconieri, Manuela Basso, Isabella Palazzolo, Iván Gómez-Mestre, H. Christoph Liedtke, Emanuela Zuccaro, Maria Pennuto, Alessandro Grapputo, Emiliano Biasini, Giovanni Spagnolli, Luisa Dalla Valle, Laura Tosatto, Kenneth H. Fischbeck, Caterina Marchioretti, Ahmed M. Hegazy, Pietro Faccioli, Giulia Boarolo, Chiara Boschelle
article en
2 citations

Abstract

How essential trans-active factors that control gene expression evolved while maintaining their ability to interact with their natural effectors and cis-active elements on DNA is a fundamental question that requires multidisciplinary approaches. Focusing on a ligand-activated transcription factor (TF), namely androgen receptor (AR), we addressed how exonic eukaryotic linear motifs (ELMs), homorepeats (HReps), and amino acids subject to post-translational modifications (PTMs) evolved in 536 species from cartilaginous fish to Homo sapiens. By combining in silico (SWISS-Model and Alphafold3), computational (molecular dynamics), and biochemical and molecular approaches, we identify functionally active ELMs present in the H. sapiens AR and trace them back to Chondrichthyes, including one in the ligand-binding domain (LBD) required for androgen binding. Moreover, we provide evidence that an ELM dynamically regulated via PTM through a cryptic phosphorylation site is an old suppressive signal from fish to human. Furthermore, we identify a similar phospho-site in the LBD of the other steroid receptors and their ancestors. These findings shed light on the timing and enduring establishment of specific ELMs and their PTMs within the steroid hormone receptor (SHR) family, while highlighting early AR-specific ELMs conserved from fish to humans, as well as ELMs that emerged later in mammals.

Nucleic Acids ResearchVol. 53(14)
National Institutes of Health (US), University of Padua (IT), University of Trento (IT), Casa Sollievo della Sofferenza (IT), Veneto Institute of Molecular Medicine (IT), Estación Biológica de Doñana (ES), Saint Camillus International University of Health and Medical Sciences (IT), Institute of Biophysics (BG), University of Palermo (AR), Istituto Nazionale di Fisica Nucleare, Sezione di Milano Bicocca (IT), University of Milano-Bicocca (IT), University of Palermo (IT)
Kennedy's Disease Association, Muscular Dystrophy Association, Association Française contre les Myopathies, Fondazione Telethon, Università degli Studi di Perugia
Openalex Percentile: Top 9%
Hormonal and reproductive studies
2.59
DOIOpen Access PDFOpenAlex
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