Understanding disorder-to-order transitions in protein-RNA complexes using molecular dynamics simulations.
TL;DR: Sarma et al. as discussed by the authors performed molecular dynamics simulations of 10 protein-RNA complexes to understand the binding governed by intrinsically disordered regions and found that most of the disordered residues are important for RNA-binding and have a transition from disordered-to-ordered conformation upon binding.
Abstract: Intrinsically disordered regions (IDRs) in proteins are characterized by their flexibilities and low complexity regions, which lack unique 3 D structures in solution IDRs play a significant role in signaling, regulation, and binding multiple partners, including DNA, RNA, and proteins Although various experiments have shown the role of disordered regions in binding with RNA, a detailed computational analysis is required to understand their binding and recognition mechanism In this work, we performed molecular dynamics simulations of 10 protein-RNA complexes to understand the binding governed by intrinsically disordered regions The simulation results show that most of the disordered regions are important for RNA-binding and have a transition from disordered-to-ordered conformation upon binding, which often contribute significantly towards the binding affinity Interestingly, most of the disordered residues are present at the interface or located as a linker between two regions having similar movements The DOT regions are overlaped or flanked with experimentally reported functionally important residues in the recognition of protein-RNA complexes This study provides additional insights for understanding the role and recognition mechanism of disordered regions in protein-RNA complexesCommunicated by Ramaswamy H Sarma
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TL;DR: MEX3A belongs to the MEX3 (Muscle EXcess) protein family consisting of four members (MEX 3A-D) in humans as discussed by the authors, and their domain structure with 2 HNRNPK homology (KH) domains mediating RNA binding and a C-terminal really interesting new gene (RING) domain that harbors E3 ligase function.
Abstract: MEX3A belongs to the MEX3 (Muscle EXcess) protein family consisting of four members (MEX3A-D) in humans. Characteristic for MEX3 proteins is their domain structure with 2 HNRNPK homology (KH) domains mediating RNA binding and a C-terminal really interesting new gene (RING) domain that harbors E3 ligase function. In agreement with their domain composition, MEX3 proteins were reported to modulate both RNA fate and protein ubiquitination. MEX3 paralogs exhibit an oncofetal expression pattern, they are severely downregulated postnatally, and re-expression is observed in various malignancies. Enforced expression of MEX3 proteins in various cancers correlates with poor prognosis, emphasizing their oncogenic potential. The latter is supported by MEX3A's impact on proliferation, self-renewal as well as migration of tumor cells in vitro and tumor growth in xenograft studies.
5 citations
21 Jan 2022
TL;DR: The anti-COVID-19 potencies of currently available antiviral drugs are reviewed, and some antiviral Drugs have been effective or prevent the spread of coronavirus.
Abstract: Viruses are the major pathogenic agents that cause various diseases. Antiviral drugs are used for the treatment of viral infections. Emergent advances of antiviral drugs are focused on two different approaches: targeting the host cell factors or the viruses themselves. Antiviral drugs that directly target the viruses include virus entry inhibitors, virus attachment inhibitors, uncoating inhibitors, protease inhibitors, polymerase inhibitors, nucleoside inhibitors, integrase inhibitors, and nucleotide reverse transcriptase. The protease inhibitors, viral DNA polymerase, and integrase inhibitors are the most commonly used antiviral drugs. Still, there are no effective antiviral drugs existing for several viral infections. Coronavirus disease-2019 (COVID-19) or SARS-CoV-2 is the newest member of the coronavirus family. No specific drugs particularly antiviral drugs have been approved for the treatment of COVID-19. Thus, it is extremely crucial to identify new drugs for the treatment of the COVID-19 outbreak. Various antiviral drugs are used for COVID-19 treatment. Currently, various drugs are under investigation to treat COVID-19 patients. Promising clinical outcomes for COVID-19 can be obtained by using alpha-interferon, remdesivir, lopinavir-ritonavir, favipiravir, ribavirin, umifenovir, oseltamivir, etc. Here, we reviewed anti-COVID-19 potencies of currently available antiviral drugs, and some antiviral drugs have been effective or prevent the spread of coronavirus.
2 citations
TL;DR: The findings show that an RNA aptamer tag to RNA molecule is an effective method to explore the functional roles of RNA-protein networks in vivo.
Abstract: Mapping networks of RNA-protein interactions in cells is essential for understanding the inner workings of many biological processes, including RNA processing, trafficking, and translation. Current in vivo methods for studying protein-RNA interactions rely mostly on purification of poly(A) transcripts, which represent only ~2-3% of total RNAs (Figure 1). Alternate robust methods for tagging RNA molecules with an RNA aptamer (e.g., MS2-, U1A- and biotin-RNA aptamer) and capturing the RNA-protein complex by the respective aptamer-specific partner are not extensively studied. Here, we describe a protocol (Figure 2) in which a biotin-RNA aptamer, referred to as the RNA mimic of biotin (RMB), was conjugated separately to two small RNA secondary structures that contribute to trafficking and translating HAC1 mRNA in the budding yeast Saccharomyces cerevisiae. The RMB-tagged RNA was expressed in yeast cells from a constitutive promoter. The biotinylated RNA bound to proteins was pulled down from the cell lysate by streptavidin agarose beads. RNA was detected by RT-PCR (Figure 3) and associated proteins by mass spectrometry (Figure 4). Our findings show that an RNA aptamer tag to RNA molecule is an effective method to explore the functional roles of RNA-protein networks in vivo.
1 citations
References
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TL;DR: It is proposed that after initial binding of 5'ppp-dsRNA to the flexibly linked CTD, co-operative tight binding of ATP and RNA to the helicase domain liberates the CARDs for downstream signaling.
565 citations
TL;DR: This work identified 1,174 binding sites within 529 HeLa cell RBPs, discovering numerous RNA-binding domains (RBDs), which display a high degree of evolutionary conservation and incidence of Mendelian mutations, suggestive of important functional roles.
462 citations
TL;DR: It is shown that the mechanism for molecular recognition requires one of the interacting proteins to anchor a specific side chain in a structurally constrained binding groove of the other protein, providing a steric constraint that helps to stabilize a native-like bound intermediate.
Abstract: We show that the mechanism for molecular recognition requires one of the interacting proteins, usually the smaller of the two, to anchor a specific side chain in a structurally constrained binding groove of the other protein, providing a steric constraint that helps to stabilize a native-like bound intermediate. We identify the anchor residues in 39 protein–protein complexes and verify that, even in the absence of their interacting partners, the anchor side chains are found in conformations similar to those observed in the bound complex. These ready-made recognition motifs correspond to surface side chains that bury the largest solvent-accessible surface area after forming the complex (≥100 A2). The existence of such anchors implies that binding pathways can avoid kinetically costly structural rearrangements at the core of the binding interface, allowing for a relatively smooth recognition process. Once anchors are docked, an induced fit process further contributes to forming the final high-affinity complex. This later stage involves flexible (solvent-exposed) side chains that latch to the encounter complex in the periphery of the binding pocket. Our results suggest that the evolutionary conservation of anchor side chains applies to the actual structure that these residues assume before the encounter complex and not just to their loci. Implications for protein docking are also discussed.
334 citations
TL;DR: The structure of the Methanococcus jannaschii TyrRS–tRNATyr–L-tyrosine complex is solved and it is revealed that this archaeal TyrRS strictly recognizes the C1-G72 base pair, whereas the bacterial TyrRS recognizes the G1-C72 in a different manner using different residues.
Abstract: The archaeal/eukaryotic tyrosyl-tRNA synthetase (TyrRS)–tRNATyr pairs do not cross-react with their bacterial counterparts. This 'orthogonal' condition is essential for using the archaeal pair to expand the bacterial genetic code. In this study, the structure of the Methanococcus jannaschii TyrRS–tRNATyr–L-tyrosine complex, solved at a resolution of 1.95 A, reveals that this archaeal TyrRS strictly recognizes the C1-G72 base pair, whereas the bacterial TyrRS recognizes the G1-C72 in a different manner using different residues. These diverse tRNA recognition modes form the basis for the orthogonality. The common tRNATyr identity determinants (the discriminator, A73 and the anticodon residues) are also recognized in manners different from those of the bacterial TyrRS. Based on this finding, we created a mutant TyrRS that aminoacylates the amber suppressor tRNA with C34 65 times more efficiently than does the wild-type enzyme.
261 citations
TL;DR: The role of disordered sequences in RBPs, their function in RNPs and protein networks, as well as their regulation by post-translational modifications and how RBP deregulation leads to disease are discussed.
190 citations