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Structural Characterization of the RNA-Binding Protein SERBP1 Reveals Intrinsic Disorder and Atypical RNA Binding Modes

RNA binding proteins (RBPs) are essential for critical biological processes such as translation regulation and mRNA processing, and misfunctions of these proteins are associated with diseases such as cancer and neurodegeneration. SERBP1 (SERPINE1 mRNA Binding Protein 1) is an RBP that comprises two...

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Autores principales: Baudin, Antoine, Moreno-Romero, Alma K., Xu, Xiaoping, Selig, Emily E., Penalva, Luiz O. F., Libich, David S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497785/
https://www.ncbi.nlm.nih.gov/pubmed/34631798
http://dx.doi.org/10.3389/fmolb.2021.744707
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author Baudin, Antoine
Moreno-Romero, Alma K.
Xu, Xiaoping
Selig, Emily E.
Penalva, Luiz O. F.
Libich, David S.
author_facet Baudin, Antoine
Moreno-Romero, Alma K.
Xu, Xiaoping
Selig, Emily E.
Penalva, Luiz O. F.
Libich, David S.
author_sort Baudin, Antoine
collection PubMed
description RNA binding proteins (RBPs) are essential for critical biological processes such as translation regulation and mRNA processing, and misfunctions of these proteins are associated with diseases such as cancer and neurodegeneration. SERBP1 (SERPINE1 mRNA Binding Protein 1) is an RBP that comprises two RG/RGG repeat regions yet lacks other recognizable RNA-binding motifs. It is involved in mRNA maturation, and translational regulation. It was initially identified as a hyaluronic acid binding protein, but recent studies have identified central roles for SERBP1 in brain function and development, especially neurogenesis and synaptogenesis. SERBP1 regulates One-carbon metabolism and epigenetic modification of histones, and increased SERBP1 expression in cancers such as leukemia, ovarian, prostate, liver and glioblastoma is correlated with poor patient outcomes. Despite these important regulatory roles for SERBP1, little is known about its structural and dynamic properties, nor about the molecular mechanisms governing its interaction with mRNA. Here, we define SERBP1 as an intrinsically disordered protein, containing highly conserved elements that were shown to be functionally important. The RNA binding activity of SERBP1 was explored using solution NMR and other biophysical techniques. The outcome of these experiments revealed that SERBP1 preferentially samples compact conformations including a central, stable α-helix and show that SERBP1 recognizes G-rich RNA sequences at the C-terminus involving the RGG box and neighboring residues. Despite the role in RNA recognition, the RGG boxes do not seem to stabilize the central helix and the central helix does not participate in RNA binding. Further, SERBP1 undergoes liquid-liquid phase separation, mediated by salt and RNA, and both RGG boxes are necessary for the efficient formation of condensed phases. Together, these results provide a foundation for understanding the molecular mechanisms of SERBP1 functions in physiological and pathological processes.
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spelling pubmed-84977852021-10-09 Structural Characterization of the RNA-Binding Protein SERBP1 Reveals Intrinsic Disorder and Atypical RNA Binding Modes Baudin, Antoine Moreno-Romero, Alma K. Xu, Xiaoping Selig, Emily E. Penalva, Luiz O. F. Libich, David S. Front Mol Biosci Molecular Biosciences RNA binding proteins (RBPs) are essential for critical biological processes such as translation regulation and mRNA processing, and misfunctions of these proteins are associated with diseases such as cancer and neurodegeneration. SERBP1 (SERPINE1 mRNA Binding Protein 1) is an RBP that comprises two RG/RGG repeat regions yet lacks other recognizable RNA-binding motifs. It is involved in mRNA maturation, and translational regulation. It was initially identified as a hyaluronic acid binding protein, but recent studies have identified central roles for SERBP1 in brain function and development, especially neurogenesis and synaptogenesis. SERBP1 regulates One-carbon metabolism and epigenetic modification of histones, and increased SERBP1 expression in cancers such as leukemia, ovarian, prostate, liver and glioblastoma is correlated with poor patient outcomes. Despite these important regulatory roles for SERBP1, little is known about its structural and dynamic properties, nor about the molecular mechanisms governing its interaction with mRNA. Here, we define SERBP1 as an intrinsically disordered protein, containing highly conserved elements that were shown to be functionally important. The RNA binding activity of SERBP1 was explored using solution NMR and other biophysical techniques. The outcome of these experiments revealed that SERBP1 preferentially samples compact conformations including a central, stable α-helix and show that SERBP1 recognizes G-rich RNA sequences at the C-terminus involving the RGG box and neighboring residues. Despite the role in RNA recognition, the RGG boxes do not seem to stabilize the central helix and the central helix does not participate in RNA binding. Further, SERBP1 undergoes liquid-liquid phase separation, mediated by salt and RNA, and both RGG boxes are necessary for the efficient formation of condensed phases. Together, these results provide a foundation for understanding the molecular mechanisms of SERBP1 functions in physiological and pathological processes. Frontiers Media S.A. 2021-09-24 /pmc/articles/PMC8497785/ /pubmed/34631798 http://dx.doi.org/10.3389/fmolb.2021.744707 Text en Copyright © 2021 Baudin, Moreno-Romero, Xu, Selig, Penalva and Libich. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Baudin, Antoine
Moreno-Romero, Alma K.
Xu, Xiaoping
Selig, Emily E.
Penalva, Luiz O. F.
Libich, David S.
Structural Characterization of the RNA-Binding Protein SERBP1 Reveals Intrinsic Disorder and Atypical RNA Binding Modes
title Structural Characterization of the RNA-Binding Protein SERBP1 Reveals Intrinsic Disorder and Atypical RNA Binding Modes
title_full Structural Characterization of the RNA-Binding Protein SERBP1 Reveals Intrinsic Disorder and Atypical RNA Binding Modes
title_fullStr Structural Characterization of the RNA-Binding Protein SERBP1 Reveals Intrinsic Disorder and Atypical RNA Binding Modes
title_full_unstemmed Structural Characterization of the RNA-Binding Protein SERBP1 Reveals Intrinsic Disorder and Atypical RNA Binding Modes
title_short Structural Characterization of the RNA-Binding Protein SERBP1 Reveals Intrinsic Disorder and Atypical RNA Binding Modes
title_sort structural characterization of the rna-binding protein serbp1 reveals intrinsic disorder and atypical rna binding modes
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497785/
https://www.ncbi.nlm.nih.gov/pubmed/34631798
http://dx.doi.org/10.3389/fmolb.2021.744707
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