Structure, Function and RNA Binding Mechanisms of the Prokaryotic Sm-like Protein Hfq

Abstract RNA-small molecule binding is a key regulatory mechanism which can stabilize 3D structures and activate molecular functions. The discovery of RNA-targeting compounds is thus a current topic of interest for novel therapies. Our work is a first attempt at bringing the scalability and generalization abilities of machine learning methods to the problem of RNA drug discovery, as well as a step towards understanding the interactions which drive binding specificity. Our tool, RNAmigos, builds and encodes a network representation of RNA structures to predict likely ligands for novel binding sites. We subject ligand predictions to virtual screening and show that we are able to place the true ligand in the 71st–73rd percentile in two decoy libraries, showing a significant improvement over several baselines, and a state of the art method. Furthermore, we observe that augmenting structural networks with non-canonical base pairing data is the only representation able to uncover a significant signal, suggesting that such interactions are a necessary source of binding specificity. We also find that pre-training with an auxiliary graph representation learning task significantly boosts performance of ligand prediction. This finding can serve as a general principle for RNA structure-function prediction when data is scarce. RNAmigos shows that RNA binding data contains structural patterns with potential for drug discovery, and provides methodological insights for possible applications to other structure-function learning tasks. The source code, data and a Web server are freely available at http://rnamigos.cs.mcgill.ca.

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Structure-function relationships in the Nab2 polyadenosine-RNA binding Zn finger protein family

Protein Science ◽

10.1002/pro.3565 ◽

2019 ◽

Vol 28 (3) ◽

pp. 513-523 ◽

Cited By ~ 7

Author(s):

Milo B. Fasken ◽

Anita H. Corbett ◽

Murray Stewart

Keyword(s):

Structure Function ◽

Rna Binding ◽

Protein Family ◽

Finger Protein

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Interaction modulation through arrays of clustered methyl-arginine protein modifications

10.1101/289041 ◽

2018 ◽

Author(s):

Jonathan Woodsmith ◽

Victoria Casado-Medrano ◽

Nouhad Benlasfer ◽

Rebecca L. Eccles ◽

Saskia Hutten ◽

...

Keyword(s):

Rna Binding ◽

Binding Protein ◽

Structural Complexity ◽

Arginine Methylation ◽

Cellular Interactions ◽

Systematic Analysis ◽

Methyl Transferase ◽

Disordered Protein ◽

Interaction Interface ◽

Binding Mechanisms

AbstractSystematic analysis of human arginine methylation identifies two distinct signaling modes; either isolated modifications akin to canonical PTM regulation, or clustered arrays within disordered protein sequence. Hundreds of proteins contain these methyl-arginine arrays and are more prone to accumulate mutations and more tightly expression-regulated than dispersed methylation targets. Arginines within an array in the highly methylated RNA binding protein SYNCRIP were experimentally shown to function in concert providing a tunable protein interaction interface. Quantitative immuno-precipitation assays defined two distinct cumulative binding mechanisms operating across 18 proximal arginine-glycine (RG) motifs in SYNCRIP. Functional binding to the methyl-transferase PRMT1 was promoted by continual arginine stretches while interaction with the methyl-binding protein SMN1 was arginine content dependent irrespective of linear position within the unstructured region. This study highlights how highly-repetitive modifiable amino acid arrays in low structural complexity regions can provide regulatory platforms, with SYNCRIP as an extreme example how arginine methylation leverages these disordered sequences to mediate cellular interactions.

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Circadian Rhythms in Fungi: Structure/Function/Evolution of Some Clock Components

Journal of Biological Rhythms ◽

10.1177/0748730419852832 ◽

2019 ◽

Vol 34 (4) ◽

pp. 364-379 ◽

Cited By ~ 4

Author(s):

Stuart Brody

Keyword(s):

Heat Shock ◽

Structure Function ◽

Protein Level ◽

Functional Significance ◽

Rna Binding ◽

Rna Binding Protein ◽

Fungal Species ◽

Motif Analysis ◽

Significant Similarity ◽

Minimum Requirements

The fungal clock, especially that in Neurospora crassa, is composed of several proteins, notably FRQ, WC-1, and WC-2, which interact at the protein level and at the level of transcription. It is shown here that regions of the FRQ that are highly conserved in many fungal species show significant similarity to regions of proteins found in the amoebae Capsaspora and Acanthamoebae. These 2 amoebae were specifically explored because they have been suggested, based on extensive evidence, to be related to precursors of the modern fungi. Those proteins in Capsaspora/Acanthamoebae with some similarity to FRQ are LARP (an RNA-binding protein), ARNT (which has a PAS motif), and heat shock factor (HSF). These regions of LARP and HSF that show similarity to FRQ are highly conserved between plants, animals, and amoeba. This suggests that these regions were present at the time of the divergence of plants, fungi, insects, and animals, and therefore, they could be plausible precursors to regions of the fungal FRQ. These particular regions of FRQ that show similarity to LARP and HSF are also of functional significance since mutations in these regions of the Neurospora FRQ led to changes in the rhythm. The FRQ proteins from 13 different species of fungi were analyzed via motif analysis (MEME), and 11 different motifs were found. This provides some understanding as to the minimum requirements for an FRQ protein. Many of these FRQ motifs can be matched up with known domains in FRQ. In addition, these 13 different species of fungi were screened for the presence/absence of 7 additional genes/proteins that play some role in fungal clocks.

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