Folding of a cyclin box: Linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor ab pocket domain
The retinoblastoma tumor suppressor (Rb) controls the proliferation, differentiation, and survival of cells in most eukaryotes with a role in the fate of stem cells. Its inactivation by mutation or oncogenic viruses is required for cellular transformation and eventually carcinogenesis. The high cons...
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2013
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v288_n26_p18923_Chemes http://hdl.handle.net/20.500.12110/paper_00219258_v288_n26_p18923_Chemes |
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paper:paper_00219258_v288_n26_p18923_Chemes2023-06-08T14:43:34Z Folding of a cyclin box: Linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor ab pocket domain Cellular transformation Conformational stabilities Human papillomavirus Ligand binding properties Multi-protein complex Retinoblastoma tumors Secondary and tertiary structures Signaling pathways Binding energy Ligands Oligomerization Oncogenic viruses Proteins Rubidium Stability Stem cells Tumors Oligomers cycline protein E7 protein p53 retinoblastoma protein transcription factor E2F article binding site carcinogenesis cell cycle regulation cell differentiation cell fate cell proliferation cell survival cell transformation circular dichroism eukaryote fluorescence spectroscopy gene mutation human in vivo study ligand binding mathematical analysis oligomerization peptide synthesis priority journal protein aggregation protein binding protein conformation protein domain protein expression protein folding protein function protein motif protein purification protein stability protein targeting protein unfolding signal transduction stem cell temperature thermodynamics tumor virus Wart virus Cyclin Fold Marginal Stability Oligomerization Protein Aggregation Protein Folding Protein Misfolding Protein Stability Retinoblastoma (Rb) Scaffold Proteins Tumor Suppressor Binding Sites Cell Differentiation Circular Dichroism Cyclins DNA-Binding Proteins E2F Transcription Factors Humans Ligands Models, Molecular Oncogene Proteins, Viral Papillomavirus E7 Proteins Protein Binding Protein Folding Protein Structure, Tertiary Retinoblastoma Protein Signal Transduction Temperature Tumor Suppressor Protein p53 Eukaryota Human papillomavirus The retinoblastoma tumor suppressor (Rb) controls the proliferation, differentiation, and survival of cells in most eukaryotes with a role in the fate of stem cells. Its inactivation by mutation or oncogenic viruses is required for cellular transformation and eventually carcinogenesis. The high conservation of the Rb cyclin fold prompted us to investigate the link between conformational stability and ligand binding properties of the RbAB pocket domain. RbAB unfolding presents a three-state transition involving cooperative secondary and tertiary structure changes and a partially folded intermediate that can oligomerize. The first transition corresponds to unfolding of the metastable B subdomain containing the binding site for the LXCXE motif present in cellular and viral targets, and the second transition corresponds to the stable A subdomain. The low thermodynamic stability of RbAB translates into a propensity to rapidly oligomerize and aggregate at 37°C (T50 = 28 min) that is suppressed by human papillomavirus E7 and E2F peptide ligands, suggesting that Rb is likely stabilized in vivo through binding to target proteins. We propose that marginal stability and associated oligomerization may be conserved for function as a "hub" protein, allowing the formation of multiprotein complexes, which could constitute a robust mechanism to retain its cell cycle regulatory role throughout evolution. Decreased stability and oligomerization are shared with the p53 tumor suppressor, suggesting a link between folding and function in these two essential cell regulators that are inactivated in most cancers and operate within multitarget signaling pathways. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. 2013 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v288_n26_p18923_Chemes http://hdl.handle.net/20.500.12110/paper_00219258_v288_n26_p18923_Chemes |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Cellular transformation Conformational stabilities Human papillomavirus Ligand binding properties Multi-protein complex Retinoblastoma tumors Secondary and tertiary structures Signaling pathways Binding energy Ligands Oligomerization Oncogenic viruses Proteins Rubidium Stability Stem cells Tumors Oligomers cycline protein E7 protein p53 retinoblastoma protein transcription factor E2F article binding site carcinogenesis cell cycle regulation cell differentiation cell fate cell proliferation cell survival cell transformation circular dichroism eukaryote fluorescence spectroscopy gene mutation human in vivo study ligand binding mathematical analysis oligomerization peptide synthesis priority journal protein aggregation protein binding protein conformation protein domain protein expression protein folding protein function protein motif protein purification protein stability protein targeting protein unfolding signal transduction stem cell temperature thermodynamics tumor virus Wart virus Cyclin Fold Marginal Stability Oligomerization Protein Aggregation Protein Folding Protein Misfolding Protein Stability Retinoblastoma (Rb) Scaffold Proteins Tumor Suppressor Binding Sites Cell Differentiation Circular Dichroism Cyclins DNA-Binding Proteins E2F Transcription Factors Humans Ligands Models, Molecular Oncogene Proteins, Viral Papillomavirus E7 Proteins Protein Binding Protein Folding Protein Structure, Tertiary Retinoblastoma Protein Signal Transduction Temperature Tumor Suppressor Protein p53 Eukaryota Human papillomavirus |
| spellingShingle |
Cellular transformation Conformational stabilities Human papillomavirus Ligand binding properties Multi-protein complex Retinoblastoma tumors Secondary and tertiary structures Signaling pathways Binding energy Ligands Oligomerization Oncogenic viruses Proteins Rubidium Stability Stem cells Tumors Oligomers cycline protein E7 protein p53 retinoblastoma protein transcription factor E2F article binding site carcinogenesis cell cycle regulation cell differentiation cell fate cell proliferation cell survival cell transformation circular dichroism eukaryote fluorescence spectroscopy gene mutation human in vivo study ligand binding mathematical analysis oligomerization peptide synthesis priority journal protein aggregation protein binding protein conformation protein domain protein expression protein folding protein function protein motif protein purification protein stability protein targeting protein unfolding signal transduction stem cell temperature thermodynamics tumor virus Wart virus Cyclin Fold Marginal Stability Oligomerization Protein Aggregation Protein Folding Protein Misfolding Protein Stability Retinoblastoma (Rb) Scaffold Proteins Tumor Suppressor Binding Sites Cell Differentiation Circular Dichroism Cyclins DNA-Binding Proteins E2F Transcription Factors Humans Ligands Models, Molecular Oncogene Proteins, Viral Papillomavirus E7 Proteins Protein Binding Protein Folding Protein Structure, Tertiary Retinoblastoma Protein Signal Transduction Temperature Tumor Suppressor Protein p53 Eukaryota Human papillomavirus Folding of a cyclin box: Linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor ab pocket domain |
| topic_facet |
Cellular transformation Conformational stabilities Human papillomavirus Ligand binding properties Multi-protein complex Retinoblastoma tumors Secondary and tertiary structures Signaling pathways Binding energy Ligands Oligomerization Oncogenic viruses Proteins Rubidium Stability Stem cells Tumors Oligomers cycline protein E7 protein p53 retinoblastoma protein transcription factor E2F article binding site carcinogenesis cell cycle regulation cell differentiation cell fate cell proliferation cell survival cell transformation circular dichroism eukaryote fluorescence spectroscopy gene mutation human in vivo study ligand binding mathematical analysis oligomerization peptide synthesis priority journal protein aggregation protein binding protein conformation protein domain protein expression protein folding protein function protein motif protein purification protein stability protein targeting protein unfolding signal transduction stem cell temperature thermodynamics tumor virus Wart virus Cyclin Fold Marginal Stability Oligomerization Protein Aggregation Protein Folding Protein Misfolding Protein Stability Retinoblastoma (Rb) Scaffold Proteins Tumor Suppressor Binding Sites Cell Differentiation Circular Dichroism Cyclins DNA-Binding Proteins E2F Transcription Factors Humans Ligands Models, Molecular Oncogene Proteins, Viral Papillomavirus E7 Proteins Protein Binding Protein Folding Protein Structure, Tertiary Retinoblastoma Protein Signal Transduction Temperature Tumor Suppressor Protein p53 Eukaryota Human papillomavirus |
| description |
The retinoblastoma tumor suppressor (Rb) controls the proliferation, differentiation, and survival of cells in most eukaryotes with a role in the fate of stem cells. Its inactivation by mutation or oncogenic viruses is required for cellular transformation and eventually carcinogenesis. The high conservation of the Rb cyclin fold prompted us to investigate the link between conformational stability and ligand binding properties of the RbAB pocket domain. RbAB unfolding presents a three-state transition involving cooperative secondary and tertiary structure changes and a partially folded intermediate that can oligomerize. The first transition corresponds to unfolding of the metastable B subdomain containing the binding site for the LXCXE motif present in cellular and viral targets, and the second transition corresponds to the stable A subdomain. The low thermodynamic stability of RbAB translates into a propensity to rapidly oligomerize and aggregate at 37°C (T50 = 28 min) that is suppressed by human papillomavirus E7 and E2F peptide ligands, suggesting that Rb is likely stabilized in vivo through binding to target proteins. We propose that marginal stability and associated oligomerization may be conserved for function as a "hub" protein, allowing the formation of multiprotein complexes, which could constitute a robust mechanism to retain its cell cycle regulatory role throughout evolution. Decreased stability and oligomerization are shared with the p53 tumor suppressor, suggesting a link between folding and function in these two essential cell regulators that are inactivated in most cancers and operate within multitarget signaling pathways. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. |
| title |
Folding of a cyclin box: Linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor ab pocket domain |
| title_short |
Folding of a cyclin box: Linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor ab pocket domain |
| title_full |
Folding of a cyclin box: Linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor ab pocket domain |
| title_fullStr |
Folding of a cyclin box: Linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor ab pocket domain |
| title_full_unstemmed |
Folding of a cyclin box: Linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor ab pocket domain |
| title_sort |
folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor ab pocket domain |
| publishDate |
2013 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v288_n26_p18923_Chemes http://hdl.handle.net/20.500.12110/paper_00219258_v288_n26_p18923_Chemes |
| _version_ |
1768542820744822784 |