Musashi-1: An Example of How Polyalanine Tracts Contribute to Self-Association in the Intrinsically Disordered Regions of RNA-Binding Proteins

Chen, Tsai-Chen; Huang, Jie Rong

doi:10.3390/ijms21072289

Cited by 15 publications

(16 citation statements)

References 67 publications

(95 reference statements)

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“…Although present in different regions, Msi1 binding sites are preferentially located at 3’ UTRs, agreeing with its described roles in translation regulation and mRNA stability. Additional Msi1 functions have been recently described that include its participation in stress granules and the formation of tau aggregates [ 67 , 68 ]. Targets of Musashi proteins have been identified in many different cell types by CLIP and RIP and encompass a variety of cancer-related processes and pathways [ 12 , 25 , 37 , 69 ].…”

Section: Discussionmentioning

confidence: 99%

The RNA-Binding Protein Musashi1 Regulates a Network of Cell Cycle Genes in Group 4 Medulloblastoma

Baroni

Guardia

Lei

et al. 2021

Cells

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Medulloblastoma is the most common malignant brain tumor in children. Treatment with surgery, irradiation, and chemotherapy has improved survival in recent years, but patients are frequently left with devastating neurocognitive and other sequelae. Patients in molecular subgroups 3 and 4 still experience a high mortality rate. To identify new pathways contributing to medulloblastoma development and create new routes for therapy, we have been studying oncogenic RNA-binding proteins. We defined Musashi1 (Msi1) as one of the main drivers of medulloblastoma development. The high expression of Msi1 is prevalent in Group 4 and correlates with poor prognosis while its knockdown disrupted cancer-relevant phenotypes. Genomic analyses (RNA-seq and RIP-seq) indicated that cell cycle and division are the main biological categories regulated by Msi1 in Group 4 medulloblastoma. The most prominent Msi1 targets include CDK2, CDK6, CCND1, CDKN2A, and CCNA1. The inhibition of Msi1 with luteolin affected the growth of CHLA-01 and CHLA-01R Group 4 medulloblastoma cells and a synergistic effect was observed when luteolin and the mitosis inhibitor, vincristine, were combined. These findings indicate that a combined therapeutic strategy (Msi1 + cell cycle/division inhibitors) could work as an alternative to treat Group 4 medulloblastoma.

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Section: Discussionmentioning

confidence: 99%

The RNA-Binding Protein Musashi1 Regulates a Network of Cell Cycle Genes in Group 4 Medulloblastoma

Baroni

Guardia

Lei

et al. 2021

Cells

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“…All constructs were purified using the same protocol, which has been described in detail elsewhere (Chen and Huang 2020). In short, transformed E. coli BL21(DE3) cells were grown at 37 °C until the O.D.…”

Section: Protein Expression and Purificationmentioning

confidence: 99%

“…The Msi-1C construct in this study (residues number 237 to 362) was cloned from a previous longer construct (Chen and Huang 2020). We removed a strongly hydrophobic region reported to contain binding sites for PABP and GLD2 (Fox, et al 2015), which is irrelevant to the present study and whose removal improves the protein's solubility.…”

Section: Dna Constructsmentioning

confidence: 99%

Phase separation driven by interchangeable properties in the intrinsically disordered regions of protein paralogs

Chiu

Sun

et al. 2022

Preprint

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Paralogs, arising from gene duplications, increase the functional diversity of proteins. Protein functions in paralog families have been extensively studied, but little is known about the roles of intrinsically disordered regions (IDRs), even though more than half of eukaryotic proteins have them. Using the RNA-binding protein Musashi family as an example, we applied multiple structural techniques and phylogenetic analysis to show how members in a paralog family have evolved their IDRs to different physicochemical properties but converge to the same function. In this example, the lower prion-like tendency of Musashi-1's IDRs, rather than Musashi-2s', is compensated by its higher α-helical propensity to assist their assembly. Without a folded structure to restraint, IDRs' sequences mutate faster along with evolution. No matter how fast they change, our work suggests that IDRs evolve different traits to a converged function, such as liquid-liquid phase separation.

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“…Of note, Msi proteins have also been associated with neurodegenerative diseases. Msi proteins have intrinsically disordered regions that could lead to their aggregation and interaction with Tau (Chen and Huang, 2020 ; Montalbano et al, 2020 ), and Msi1/2 were found to form oligomers in brains of patients with Alzheimer's disease, amyotrophic lateral sclerosis, and frontotemporal dementia (Sengupta et al, 2018 ; Montalbano et al, 2020 ).…”

Section: The Musashi Rna Binding Protein Family As Master Regulators Of Neuronal Developmentmentioning

confidence: 99%

The Fine Art of Writing a Message: RNA Metabolism in the Shaping and Remodeling of the Nervous System

Landínez-Macías

Urwyler

2021

Front. Mol. Neurosci.

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Neuronal morphogenesis, integration into circuits, and remodeling of synaptic connections occur in temporally and spatially defined steps. Accordingly, the expression of proteins and specific protein isoforms that contribute to these processes must be controlled quantitatively in time and space. A wide variety of post-transcriptional regulatory mechanisms, which act on pre-mRNA and mRNA molecules contribute to this control. They are thereby critically involved in physiological and pathophysiological nervous system development, function, and maintenance. Here, we review recent findings on how mRNA metabolism contributes to neuronal development, from neural stem cell maintenance to synapse specification, with a particular focus on axon growth, guidance, branching, and synapse formation. We emphasize the role of RNA-binding proteins, and highlight their emerging roles in the poorly understood molecular processes of RNA editing, alternative polyadenylation, and temporal control of splicing, while also discussing alternative splicing, RNA localization, and local translation. We illustrate with the example of the evolutionary conserved Musashi protein family how individual RNA-binding proteins are, on the one hand, acting in different processes of RNA metabolism, and, on the other hand, impacting multiple steps in neuronal development and circuit formation. Finally, we provide links to diseases that have been associated with the malfunction of RNA-binding proteins and disrupted post-transcriptional regulation.

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Musashi-1: An Example of How Polyalanine Tracts Contribute to Self-Association in the Intrinsically Disordered Regions of RNA-Binding Proteins

Cited by 15 publications

References 67 publications

The RNA-Binding Protein Musashi1 Regulates a Network of Cell Cycle Genes in Group 4 Medulloblastoma

The RNA-Binding Protein Musashi1 Regulates a Network of Cell Cycle Genes in Group 4 Medulloblastoma

Phase separation driven by interchangeable properties in the intrinsically disordered regions of protein paralogs

The Fine Art of Writing a Message: RNA Metabolism in the Shaping and Remodeling of the Nervous System

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