Phosphorylation regulates the bound structure of an intrinsically disordered protein: The p53-TAZ2 case
Disordered regions and Intrinsically Disordered Proteins (IDPs) are involved in critical cellular processes and may acquire a stable three-dimensional structure only upon binding to their partners. IDPs may follow a folding-after-binding process, known as induced folding, or a folding-before-binding...
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paper:paper_19326203_v11_n1_p_Ithuralde2023-06-08T16:30:33Z Phosphorylation regulates the bound structure of an intrinsically disordered protein: The p53-TAZ2 case Ithuralde, Raul Esteban Turjanski, Adrián Gustavo intrinsically disordered protein protein p53 bone sialoprotein (35-62), human intrinsically disordered protein peptide fragment protein binding protein p53 sialoglycoprotein Article binding affinity binding site complex formation controlled study molecular recognition protein binding protein determination protein folding protein phosphorylation protein processing protein protein interaction structure analysis chemistry genetic transcription genetics human metabolism molecular dynamics molecular genetics phosphorylation protein motif protein processing protein secondary structure protein tertiary structure Amino Acid Motifs Binding Sites Humans Intrinsically Disordered Proteins Molecular Dynamics Simulation Molecular Sequence Data Peptide Fragments Phosphorylation Protein Binding Protein Folding Protein Processing, Post-Translational Protein Structure, Secondary Protein Structure, Tertiary Sialoglycoproteins Transcription, Genetic Tumor Suppressor Protein p53 Disordered regions and Intrinsically Disordered Proteins (IDPs) are involved in critical cellular processes and may acquire a stable three-dimensional structure only upon binding to their partners. IDPs may follow a folding-after-binding process, known as induced folding, or a folding-before-binding process, known as conformational selection. The transcription factor p53 is involved in the regulation of cellular events that arise upon stress or DNA damage. The p53 domain structure is composed of an N-terminal transactivation domain (p53TAD), a DNA Binding Domain and a tetramerization domain. The activity of TAD is tightly regulated by interactions with cofactors, inhibitors and phosphorylation. To initiate transcription, p53TAD binds to the TAZ2 domain of CBP, a co-transcription factor, and undergoes a folding and binding process, as revealed by the recent NMR structure of the complex. The activity of p53 is regulated by phosphorylation at multiple sites on the TAD domain and recent studies have shown that modifications at three residues affect the binding towards TAZ2. However, we still do not know how these phosphorylations affect the structure of the bound state and, therefore, how they regulate the p53 function. In this work, we have used computational simulations to understand how phosphorylation affects the structure of the p53TAD: TAZ2 complex and regulates the recognition mechanism. Phosphorylation has been proposed to enhance binding by direct interaction with the folded protein or by changing the unbound conformation of IDPs, for example by pre-folding the protein favoring the recognition mechanism. Here, we show an interesting turn in the p53 case: phosphorylation mainly affects the bound structure of p53TAD, highlighting the complexity of IDP protein-protein interactions. Our results are in agreement with previous experimental studies, allowing a clear picture of how p53 is regulated by phosphorylation and giving new insights into how post-translational modifications can regulate the function of IDPs. © 2016 Ithuralde, Turjanski. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Fil:Ithuralde, R.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Turjanski, A.G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2016 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v11_n1_p_Ithuralde http://hdl.handle.net/20.500.12110/paper_19326203_v11_n1_p_Ithuralde |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
intrinsically disordered protein protein p53 bone sialoprotein (35-62), human intrinsically disordered protein peptide fragment protein binding protein p53 sialoglycoprotein Article binding affinity binding site complex formation controlled study molecular recognition protein binding protein determination protein folding protein phosphorylation protein processing protein protein interaction structure analysis chemistry genetic transcription genetics human metabolism molecular dynamics molecular genetics phosphorylation protein motif protein processing protein secondary structure protein tertiary structure Amino Acid Motifs Binding Sites Humans Intrinsically Disordered Proteins Molecular Dynamics Simulation Molecular Sequence Data Peptide Fragments Phosphorylation Protein Binding Protein Folding Protein Processing, Post-Translational Protein Structure, Secondary Protein Structure, Tertiary Sialoglycoproteins Transcription, Genetic Tumor Suppressor Protein p53 |
| spellingShingle |
intrinsically disordered protein protein p53 bone sialoprotein (35-62), human intrinsically disordered protein peptide fragment protein binding protein p53 sialoglycoprotein Article binding affinity binding site complex formation controlled study molecular recognition protein binding protein determination protein folding protein phosphorylation protein processing protein protein interaction structure analysis chemistry genetic transcription genetics human metabolism molecular dynamics molecular genetics phosphorylation protein motif protein processing protein secondary structure protein tertiary structure Amino Acid Motifs Binding Sites Humans Intrinsically Disordered Proteins Molecular Dynamics Simulation Molecular Sequence Data Peptide Fragments Phosphorylation Protein Binding Protein Folding Protein Processing, Post-Translational Protein Structure, Secondary Protein Structure, Tertiary Sialoglycoproteins Transcription, Genetic Tumor Suppressor Protein p53 Ithuralde, Raul Esteban Turjanski, Adrián Gustavo Phosphorylation regulates the bound structure of an intrinsically disordered protein: The p53-TAZ2 case |
| topic_facet |
intrinsically disordered protein protein p53 bone sialoprotein (35-62), human intrinsically disordered protein peptide fragment protein binding protein p53 sialoglycoprotein Article binding affinity binding site complex formation controlled study molecular recognition protein binding protein determination protein folding protein phosphorylation protein processing protein protein interaction structure analysis chemistry genetic transcription genetics human metabolism molecular dynamics molecular genetics phosphorylation protein motif protein processing protein secondary structure protein tertiary structure Amino Acid Motifs Binding Sites Humans Intrinsically Disordered Proteins Molecular Dynamics Simulation Molecular Sequence Data Peptide Fragments Phosphorylation Protein Binding Protein Folding Protein Processing, Post-Translational Protein Structure, Secondary Protein Structure, Tertiary Sialoglycoproteins Transcription, Genetic Tumor Suppressor Protein p53 |
| description |
Disordered regions and Intrinsically Disordered Proteins (IDPs) are involved in critical cellular processes and may acquire a stable three-dimensional structure only upon binding to their partners. IDPs may follow a folding-after-binding process, known as induced folding, or a folding-before-binding process, known as conformational selection. The transcription factor p53 is involved in the regulation of cellular events that arise upon stress or DNA damage. The p53 domain structure is composed of an N-terminal transactivation domain (p53TAD), a DNA Binding Domain and a tetramerization domain. The activity of TAD is tightly regulated by interactions with cofactors, inhibitors and phosphorylation. To initiate transcription, p53TAD binds to the TAZ2 domain of CBP, a co-transcription factor, and undergoes a folding and binding process, as revealed by the recent NMR structure of the complex. The activity of p53 is regulated by phosphorylation at multiple sites on the TAD domain and recent studies have shown that modifications at three residues affect the binding towards TAZ2. However, we still do not know how these phosphorylations affect the structure of the bound state and, therefore, how they regulate the p53 function. In this work, we have used computational simulations to understand how phosphorylation affects the structure of the p53TAD: TAZ2 complex and regulates the recognition mechanism. Phosphorylation has been proposed to enhance binding by direct interaction with the folded protein or by changing the unbound conformation of IDPs, for example by pre-folding the protein favoring the recognition mechanism. Here, we show an interesting turn in the p53 case: phosphorylation mainly affects the bound structure of p53TAD, highlighting the complexity of IDP protein-protein interactions. Our results are in agreement with previous experimental studies, allowing a clear picture of how p53 is regulated by phosphorylation and giving new insights into how post-translational modifications can regulate the function of IDPs. © 2016 Ithuralde, Turjanski. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| author |
Ithuralde, Raul Esteban Turjanski, Adrián Gustavo |
| author_facet |
Ithuralde, Raul Esteban Turjanski, Adrián Gustavo |
| author_sort |
Ithuralde, Raul Esteban |
| title |
Phosphorylation regulates the bound structure of an intrinsically disordered protein: The p53-TAZ2 case |
| title_short |
Phosphorylation regulates the bound structure of an intrinsically disordered protein: The p53-TAZ2 case |
| title_full |
Phosphorylation regulates the bound structure of an intrinsically disordered protein: The p53-TAZ2 case |
| title_fullStr |
Phosphorylation regulates the bound structure of an intrinsically disordered protein: The p53-TAZ2 case |
| title_full_unstemmed |
Phosphorylation regulates the bound structure of an intrinsically disordered protein: The p53-TAZ2 case |
| title_sort |
phosphorylation regulates the bound structure of an intrinsically disordered protein: the p53-taz2 case |
| publishDate |
2016 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v11_n1_p_Ithuralde http://hdl.handle.net/20.500.12110/paper_19326203_v11_n1_p_Ithuralde |
| work_keys_str_mv |
AT ithuralderaulesteban phosphorylationregulatestheboundstructureofanintrinsicallydisorderedproteinthep53taz2case AT turjanskiadriangustavo phosphorylationregulatestheboundstructureofanintrinsicallydisorderedproteinthep53taz2case |
| _version_ |
1768545258947215360 |