ArreSTick motif controls β-arrestin-binding stability and extends phosphorylation-dependent β-arrestin interactions to non-receptor proteins
András Dávid Tóth,
Eszter Soltész-Katona,
Katalin Kis,
Viktor Guti,
Sharon Gilzer,
Susanne Prokop,
Roxána Boros,
Ádám Misák,
András Balla,
Péter Várnai,
Lilla Turiák,
András Ács,
László Drahos,
Asuka Inoue,
László Hunyady,
Gábor Turu
Affiliations
András Dávid Tóth
Institute of Molecular Life Sciences, Centre of Excellence of the Hungarian Academy of Sciences, HUN-REN Research Centre for Natural Sciences, Magyar Tudósok krt. 2., 1117 Budapest, Hungary; Department of Internal Medicine and Haematology, Semmelweis University, Szentkirályi street 46, 1088 Budapest, Hungary
Eszter Soltész-Katona
Institute of Molecular Life Sciences, Centre of Excellence of the Hungarian Academy of Sciences, HUN-REN Research Centre for Natural Sciences, Magyar Tudósok krt. 2., 1117 Budapest, Hungary; Department of Physiology, Semmelweis University, Tűzoltó street 37-47, 1094 Budapest, Hungary
Katalin Kis
Department of Physiology, Semmelweis University, Tűzoltó street 37-47, 1094 Budapest, Hungary
Viktor Guti
Department of Physiology, Semmelweis University, Tűzoltó street 37-47, 1094 Budapest, Hungary
Sharon Gilzer
Department of Physiology, Semmelweis University, Tűzoltó street 37-47, 1094 Budapest, Hungary
Susanne Prokop
Department of Physiology, Semmelweis University, Tűzoltó street 37-47, 1094 Budapest, Hungary
Roxána Boros
Department of Physiology, Semmelweis University, Tűzoltó street 37-47, 1094 Budapest, Hungary
Ádám Misák
Department of Physiology, Semmelweis University, Tűzoltó street 37-47, 1094 Budapest, Hungary
András Balla
Department of Physiology, Semmelweis University, Tűzoltó street 37-47, 1094 Budapest, Hungary; HUN-REN SE Hungarian Research Network Laboratory of Molecular Physiology, Budapest, Hungary
Péter Várnai
Department of Physiology, Semmelweis University, Tűzoltó street 37-47, 1094 Budapest, Hungary; HUN-REN SE Hungarian Research Network Laboratory of Molecular Physiology, Budapest, Hungary
Lilla Turiák
Institute of Organic Chemistry, HUN-REN Research Centre for Natural Sciences, Magyar Tudósok krt. 2., 1117 Budapest, Hungary
András Ács
Institute of Organic Chemistry, HUN-REN Research Centre for Natural Sciences, Magyar Tudósok krt. 2., 1117 Budapest, Hungary
László Drahos
Institute of Organic Chemistry, HUN-REN Research Centre for Natural Sciences, Magyar Tudósok krt. 2., 1117 Budapest, Hungary
Asuka Inoue
Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
László Hunyady
Institute of Molecular Life Sciences, Centre of Excellence of the Hungarian Academy of Sciences, HUN-REN Research Centre for Natural Sciences, Magyar Tudósok krt. 2., 1117 Budapest, Hungary; Department of Physiology, Semmelweis University, Tűzoltó street 37-47, 1094 Budapest, Hungary; Corresponding author
Gábor Turu
Institute of Molecular Life Sciences, Centre of Excellence of the Hungarian Academy of Sciences, HUN-REN Research Centre for Natural Sciences, Magyar Tudósok krt. 2., 1117 Budapest, Hungary; Department of Physiology, Semmelweis University, Tűzoltó street 37-47, 1094 Budapest, Hungary; Corresponding author
Summary: The binding and function of β-arrestins are regulated by specific phosphorylation motifs present in G protein-coupled receptors (GPCRs). However, the exact arrangement of phosphorylated amino acids responsible for establishing a stable interaction remains unclear. We employ a 1D sequence convolution model trained on GPCRs with established β-arrestin-binding properties. With this approach, amino acid motifs characteristic of GPCRs that form stable interactions with β-arrestins can be identified, a pattern that we name “arreSTick.” Intriguingly, the arreSTick pattern is also present in numerous non-receptor proteins. Using proximity biotinylation assay and mass spectrometry analysis, we demonstrate that the arreSTick motif controls the interaction between many non-receptor proteins and β-arrestin2. The HIV-1 Tat-specific factor 1 (HTSF1 or HTATSF1), a nuclear transcription factor, contains the arreSTick pattern, and its subcellular localization is influenced by β-arrestin2. Our findings unveil a broader role for β-arrestins in phosphorylation-dependent interactions, extending beyond GPCRs to encompass non-receptor proteins as well.
