Jul 26 2022 Musashi-1 RNA-binding protein's role in RNA recognition

In this contribution we study the association complexes of the RNA-binding protein Musashi-1 with different RNA motifs, using molecular dynamics simulations

Association complexes of Musashi-1 RBD1 and RBD2 with the canonical target RNA GUAGU

Musashi-1 (MSI1), an RNA-binding protein, plays a pivotal role in maintaining and self-renewal of neural progenitor and stem cells. Intriguingly, it has been demonstrated to enhance Zika virus (ZIKV) replication, emphasizing the significance of MSI1:RNA complexes in ZIKV-induced neurotropism.

In this study, we employ computational modeling to assess the association complexes formed between the RNA-binding protein MSI1 and various target RNAs. MSI1 has two RNA-binding domains, each displaying distinct affinities for binding single-stranded RNA molecules. Utilizing molecular dynamics simulations alongside binding free energy calculations, we delve into the intricacies of MSI1:RNA complexes. This investigation holds the key to unraveling MSI1's role in congenital neuropathology, notably microcephaly.

Collaborating with esteemed researchers Thanyada Rungrotmongkol and Nitchakan Darai from Chulalongkorn University, as well as Peter Wolschann from Universität Wien, this study advances our understanding of RNA-protein interactions with profound implications for both biology and disease.

Abstract

The Musashi (MSI) family of RNA-binding proteins, comprising the two homologs Musashi-1 (MSI1) and Musashi-2 (MSI2), typically regulates translation and is involved in cell proliferation and tumorigenesis. MSI proteins contain two ribonucleoprotein-like RNA-binding domains, RBD1 and RBD2, that bind single-stranded RNA motifs with a central UAG trinucleotide with high affinity and specificity. The finding that MSI also promotes the replication of Zika virus, a neurotropic Flavivirus, has triggered further investigations of the biochemical principles behind MSI–RNA interactions. However, a detailed molecular understanding of the specificity of MSI RBD1/2 interaction with RNA is still missing. Here, we performed computational studies of MSI1–RNA association complexes, investigating different RNA pentamer motifs using molecular dynamics simulations with binding free energy calculations based on the solvated interaction energy method. Simulations with Alphafold2 suggest that predicted MSI protein structures are highly similar to experimentally determined structures. The binding free energies show that two out of four RNA pentamers exhibit a considerably higher binding affinity to MSI1 RBD1 and RBD2, respectively. The obtained structural information on MSI1 RBD1 and RBD2 will be useful for a detailed functional and mechanistic understanding of this type of RNA–protein interactions.

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Citation

Theoretical studies on RNA recognition by Musashi 1 RNA–binding protein
Nitchakan Darai, Panupong Mahalapbutr, Peter Wolschann, Vannajan Sanghiran Lee, Michael T. Wolﬁnger, Thanyada Rungrotmongkol
Sci. Rep. 12:12137 (2022) | doi:10.1038/s41598-022-16252-w | PDF

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