Short linear motif core and flanking regions modulate retinoblastoma protein binding affinity and specificity
Pocket proteins retinoblastoma (pRb), p107 and p130 are negative regulators of cellular proliferation and multifunctional proteins regulating development, differentiation and chromatin structure. The retinoblastoma protein is a potent tumor suppressor mutated in a wide range of human cancers, and on...
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2018
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_17410126_v31_n3_p69_Palopoli http://hdl.handle.net/20.500.12110/paper_17410126_v31_n3_p69_Palopoli |
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paper:paper_17410126_v31_n3_p69_Palopoli2023-06-08T16:26:59Z Short linear motif core and flanking regions modulate retinoblastoma protein binding affinity and specificity cell cycle checkpoint flanking regions LxCxE motif retinoblastoma SLiM Binding energy Binding sites Cell proliferation Oncogenic viruses Cell cycle Flanking regions LxCxE motif Retinoblastoma SLiM Proteins lxcxe protein protein retinoblastoma protein unclassified drug viral protein protein binding retinoblastoma protein binding affinity convergent evolution G1 phase cell cycle checkpoint human nonhuman priority journal protein binding protein determination protein function protein interaction protein localization protein motif protein phosphorylation Review animal chemistry enzyme specificity metabolism molecular model protein motif rat Amino Acid Motifs Animals Humans Models, Molecular Protein Binding Rats Retinoblastoma Protein Substrate Specificity Pocket proteins retinoblastoma (pRb), p107 and p130 are negative regulators of cellular proliferation and multifunctional proteins regulating development, differentiation and chromatin structure. The retinoblastoma protein is a potent tumor suppressor mutated in a wide range of human cancers, and oncogenic viruses often interfere with cell cycle regulation by inactivating pRb. The LxCxE and pRb AB groove short linear motifs (SLiMs) are key to many pocket protein mediated interactions including host and viral partners. A review of available experimental evidence reveals that several core residues composing each motif instance are determinants for binding. In the LxCxE motif, a fourth hydrophobic position that might allow variable spacing is required for binding. In both motifs, flanking regions including charged stretches and phosphorylation sites can fine-tune the binding affinity and specificity of pocket protein SLiM-mediated interactions. Flanking regions can modulate pocket protein binding specificity, or tune the high affinity interactions of viral proteins that hijack the pRb network. The location of SLiMs within intrinsically disordered regions allows faster evolutionary rates that enable viruses to acquire a functional variant of the core motif by convergent evolution, and subsequently test numerous combinations of flanking regions towards maximizing interaction specificity and affinity. This knowledge can guide future efforts directed at the design of peptide-based compounds that can target pocket proteins to regulate the G1/S cell cycle checkpoint or impair viral mediated pRb inactivation. © 2017 The Author. Published by Oxford University Press. All rights reserved. 2018 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_17410126_v31_n3_p69_Palopoli http://hdl.handle.net/20.500.12110/paper_17410126_v31_n3_p69_Palopoli |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
cell cycle checkpoint flanking regions LxCxE motif retinoblastoma SLiM Binding energy Binding sites Cell proliferation Oncogenic viruses Cell cycle Flanking regions LxCxE motif Retinoblastoma SLiM Proteins lxcxe protein protein retinoblastoma protein unclassified drug viral protein protein binding retinoblastoma protein binding affinity convergent evolution G1 phase cell cycle checkpoint human nonhuman priority journal protein binding protein determination protein function protein interaction protein localization protein motif protein phosphorylation Review animal chemistry enzyme specificity metabolism molecular model protein motif rat Amino Acid Motifs Animals Humans Models, Molecular Protein Binding Rats Retinoblastoma Protein Substrate Specificity |
| spellingShingle |
cell cycle checkpoint flanking regions LxCxE motif retinoblastoma SLiM Binding energy Binding sites Cell proliferation Oncogenic viruses Cell cycle Flanking regions LxCxE motif Retinoblastoma SLiM Proteins lxcxe protein protein retinoblastoma protein unclassified drug viral protein protein binding retinoblastoma protein binding affinity convergent evolution G1 phase cell cycle checkpoint human nonhuman priority journal protein binding protein determination protein function protein interaction protein localization protein motif protein phosphorylation Review animal chemistry enzyme specificity metabolism molecular model protein motif rat Amino Acid Motifs Animals Humans Models, Molecular Protein Binding Rats Retinoblastoma Protein Substrate Specificity Short linear motif core and flanking regions modulate retinoblastoma protein binding affinity and specificity |
| topic_facet |
cell cycle checkpoint flanking regions LxCxE motif retinoblastoma SLiM Binding energy Binding sites Cell proliferation Oncogenic viruses Cell cycle Flanking regions LxCxE motif Retinoblastoma SLiM Proteins lxcxe protein protein retinoblastoma protein unclassified drug viral protein protein binding retinoblastoma protein binding affinity convergent evolution G1 phase cell cycle checkpoint human nonhuman priority journal protein binding protein determination protein function protein interaction protein localization protein motif protein phosphorylation Review animal chemistry enzyme specificity metabolism molecular model protein motif rat Amino Acid Motifs Animals Humans Models, Molecular Protein Binding Rats Retinoblastoma Protein Substrate Specificity |
| description |
Pocket proteins retinoblastoma (pRb), p107 and p130 are negative regulators of cellular proliferation and multifunctional proteins regulating development, differentiation and chromatin structure. The retinoblastoma protein is a potent tumor suppressor mutated in a wide range of human cancers, and oncogenic viruses often interfere with cell cycle regulation by inactivating pRb. The LxCxE and pRb AB groove short linear motifs (SLiMs) are key to many pocket protein mediated interactions including host and viral partners. A review of available experimental evidence reveals that several core residues composing each motif instance are determinants for binding. In the LxCxE motif, a fourth hydrophobic position that might allow variable spacing is required for binding. In both motifs, flanking regions including charged stretches and phosphorylation sites can fine-tune the binding affinity and specificity of pocket protein SLiM-mediated interactions. Flanking regions can modulate pocket protein binding specificity, or tune the high affinity interactions of viral proteins that hijack the pRb network. The location of SLiMs within intrinsically disordered regions allows faster evolutionary rates that enable viruses to acquire a functional variant of the core motif by convergent evolution, and subsequently test numerous combinations of flanking regions towards maximizing interaction specificity and affinity. This knowledge can guide future efforts directed at the design of peptide-based compounds that can target pocket proteins to regulate the G1/S cell cycle checkpoint or impair viral mediated pRb inactivation. © 2017 The Author. Published by Oxford University Press. All rights reserved. |
| title |
Short linear motif core and flanking regions modulate retinoblastoma protein binding affinity and specificity |
| title_short |
Short linear motif core and flanking regions modulate retinoblastoma protein binding affinity and specificity |
| title_full |
Short linear motif core and flanking regions modulate retinoblastoma protein binding affinity and specificity |
| title_fullStr |
Short linear motif core and flanking regions modulate retinoblastoma protein binding affinity and specificity |
| title_full_unstemmed |
Short linear motif core and flanking regions modulate retinoblastoma protein binding affinity and specificity |
| title_sort |
short linear motif core and flanking regions modulate retinoblastoma protein binding affinity and specificity |
| publishDate |
2018 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_17410126_v31_n3_p69_Palopoli http://hdl.handle.net/20.500.12110/paper_17410126_v31_n3_p69_Palopoli |
| _version_ |
1768542807835803648 |