Allosteric mechanism for SL RNA recognition by polypyrimidine tract binding protein RRM1: An atomistic MD simulation and network-based study

Han, Zhongjie; Wu, Zhixiang; Gong, Weikang; Zhou, Wenxue; Chen, Lei; Li, Chunhua

doi:10.1016/j.ijbiomac.2022.08.181

Cited by 4 publications

(4 citation statements)

References 36 publications

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“…As described above, a C-terminal α3 helix folds upon binding to an RNA hairpin in the ECMV IRES, and this helix was critical for PTBP1-mediated enhancement of IRES activity in vitro [ 68 ]. While this has not yet been explored in vivo, this study and another [ 72 ] have revealed a potential mechanism of domain-specific RRM1 function in PTBP1-dependent IRES initiated translation, the functional implications of which are important to elucidate in an in vivo setting.…”

Section: The Rrm Domains Of Ptbp1 Have a Unique Contribution To Ptbp1...mentioning

confidence: 90%

“…Intriguingly, several recent studies have demonstrated that the C-terminal region of the RRM1 domain is a critical allosteric regulator of RNA binding [ 68 , 72 ]. These studies identified a C-terminal α-helix (termed the α3 helix) comprised of residues 144–154 that folds upon binding to the stem-loop region of the encephalomyocarditis virus (ECMV) IRES element, but does not directly interact with RNA.…”

Section: The Rrm Domains Of Ptbp1 Are Structurally Heterogenousmentioning

confidence: 99%

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Reviewing PTBP1 Domain Modularity in the Pre-Genomic Era: A Foundation to Guide the Next Generation of Exploring PTBP1 Structure–Function Relationships

Carico

Placzek

2023

IJMS

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Polypyrimidine tract binding protein 1 (PTBP1) is one of the most well-described RNA binding proteins, known initially for its role as a splicing repressor before later studies revealed its numerous roles in RNA maturation, stability, and translation. While PTBP1’s various biological roles have been well-described, it remains unclear how its four RNA recognition motif (RRM) domains coordinate these functions. The early PTBP1 literature saw extensive effort placed in detailing structures of each of PTBP1’s RRMs, as well as their individual RNA sequence and structure preferences. However, limitations in high-throughput and high-resolution genomic approaches (i.e., next-generation sequencing had not yet been developed) precluded the functional translation of these findings into a mechanistic understanding of each RRM’s contribution to overall PTBP1 function. With the emergence of new technologies, it is now feasible to begin elucidating the individual contributions of each RRM to PTBP1 biological functions. Here, we review all the known literature describing the apo and RNA bound structures of each of PTBP1’s RRMs, as well as the emerging literature describing the dependence of specific RNA processing events on individual RRM domains. Our goal is to provide a framework of the structure–function context upon which to facilitate the interpretation of future studies interrogating the dynamics of PTBP1 function.

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Section: The Rrm Domains Of Ptbp1 Have a Unique Contribution To Ptbp1...mentioning

confidence: 90%

Section: The Rrm Domains Of Ptbp1 Are Structurally Heterogenousmentioning

confidence: 99%

Reviewing PTBP1 Domain Modularity in the Pre-Genomic Era: A Foundation to Guide the Next Generation of Exploring PTBP1 Structure–Function Relationships

Carico

Placzek

2023

IJMS

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“…Interest in RNA's allosteric mechanisms 31,45 has recently surged, especially concerning its role in various biological processes such as RNA viruses, bacterial RNA regulation, and the emergence of RNA vaccines. 46−48 Similar to allosteric proteins, 49 allosteric RNAs 50−52 control their activities through effector binding at a distant site, affecting functions like ligand binding, 53,54 RNA splicing, 55 riboswitch regulation, 50,56 and ribozyme activities. 57−59 This communication was traditionally thought to involve significant conformational transitions, thereby shifting the free energy basin of the conformational state.…”

Section: The Journal Of Physical Chemistry Lettersmentioning

confidence: 99%

“…Interest in RNA’s allosteric mechanisms , has recently surged, especially concerning its role in various biological processes such as RNA viruses, bacterial RNA regulation, and the emergence of RNA vaccines. − Similar to allosteric proteins, allosteric RNAs − control their activities through effector binding at a distant site, affecting functions like ligand binding, , RNA splicing, riboswitch regulation, , and ribozyme activities. − This communication was traditionally thought to involve significant conformational transitions, thereby shifting the free energy basin of the conformational state . Alternatively, it is plausible that the conformation induced by effector binding simply alters the broadness of the free energy minimum without substantially changing the position of the basin in the conformational phase space, a concept now recognized as dynamic allostery. − However, contrasting two RNA systems (BIV and HIV TAR–TAT complexes), this study reveals that effector-driven allostery can be either entropic or enthalpic.…”

mentioning

confidence: 99%

RNA’s Dynamic Conformational Selection and Entropic Allosteric Mechanism in Controlling Cascade Protein Binding Events

Chakraborty,

Samant,

Sarkar

et al. 2024

J. Phys. Chem. Lett.

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In the TAR RNA of immunodeficiency viruses, an allosteric communication exists between a distant loop and a bulge. The bulge interacts with the TAT protein vital for transactivating viral RNA, while the loop interacts with cyclin-T1, contingent on TAT binding. Through extensive atomistic and free energy simulations, we investigate TAR–TAT binding in nonpathogenic bovine immunodeficiency virus (BIV) and pathogenic human immunodeficiency virus (HIV). Thermodynamic analysis reveals enthalpically driven binding in BIV and entropically favored binding in HIV. The broader global basin in HIV is attributed to binding-induced loop fluctuation, corroborated by nuclear magnetic resonance (NMR), indicating classical entropic allostery onset. While this loop fluctuation affects the TAT binding affinity, it generates a binding-competent conformation that aids subsequent effector (cyclin-T1) binding. This study underscores how two structurally similar apo-RNA scaffolds adopt distinct conformational selection mechanisms to drive enthalpic and entropic allostery, influencing protein affinity in the signaling cascade.

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RNAfcg: RNA Flexibility Prediction Based on Topological Centrality and Global Features

Chang,

Liu,

et al. 2024

J. Chem. Inf. Model.

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The dynamics of RNAs are related intimately to their functions. Molecular flexibility, as a starting point for understanding their dynamics, has been utilized to predict many characteristics associated with their functions. Since the experimental measurement methods are time-consuming and laborintensive, it is urgently needed to develop reliable theoretical methods to predict RNA flexibility. In this work, we develop an effective machine learning method, RNAfcg, to predict RNA flexibility, where the Random Forest (RF) is trained by features including the topological centralities, flexibility−rigidity index, and global characteristics first introduced by us, as well as some traditional sequence and structural features. The analyses show that the three types of features introduced first have significant contributions to RNA flexibility prediction, among which the topological type contributes the most, which indicates the importance of structural topology in determining RNA flexibility. The performance comparison indicates that RNAfcg outperforms the state-of-the-art machine learning methods and the commonly used Gaussian Network Model (GNM) models, achieving a much higher Pearson correlation coefficient (PCC) of 0.6619 on the test data set. This work is helpful for understanding RNA dynamics and can be used to predict RNA function information. The source code is available at https://github.com/ChunhuaLab/RNAfcg/.

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Allosteric mechanism for SL RNA recognition by polypyrimidine tract binding protein RRM1: An atomistic MD simulation and network-based study

Cited by 4 publications

References 36 publications

Reviewing PTBP1 Domain Modularity in the Pre-Genomic Era: A Foundation to Guide the Next Generation of Exploring PTBP1 Structure–Function Relationships

Reviewing PTBP1 Domain Modularity in the Pre-Genomic Era: A Foundation to Guide the Next Generation of Exploring PTBP1 Structure–Function Relationships

RNA’s Dynamic Conformational Selection and Entropic Allosteric Mechanism in Controlling Cascade Protein Binding Events

RNAfcg: RNA Flexibility Prediction Based on Topological Centrality and Global Features

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