Intrinsically-Disordered Regions Governs Protein RNA Binding - review

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Article: Intra- and Inter-Molecular Regulation by Intrinsically-Disordered Regions Governs PUF Protein RNA Binding

Introduction

PUF (Pumilio and FBF) proteins are a large family of RNA-binding proteins that play crucial roles in various biological processes, including development, translation, and mRNA stability. These proteins are characterized by a conserved RNA-binding domain (RBD) that recognizes and binds specific RNA sequences. However, the regulation of PUF protein RNA-binding activity is complex and involves both intra- and intermolecular interactions.

Intrinsically disordered regions (IDRs) are prevalent in eukaryotic proteomes and are often found in RNA-binding proteins. IDRs lack a stable three-dimensional structure and can adopt a variety of conformations, which allows them to engage in dynamic interactions with other molecules. These interactions can modulate protein function, including RNA-binding activity.


RNA-binding proteins have a modular structure where intrinsically disordered regions (IDRs) can work as linkers connecting modules within a single protein or as connectors that mediate interactions between several proteins and/or RNA.


As IDR (proteins) guides information to the RNA. This violates Francis Crick's Central Dogma of neo darwinism.



Central dogma. The central dogma of molecular biology is a theory stating that genetic information flows only in one direction, from DNA, to RNA, to protein, or RNA directly to protein.


Regulation of PUF Protein RNA Binding by IDRs

This recent study by Wang et al. (2023) investigated the role of IDRs in regulating the RNA-binding activity of fem-3 binding factor-2 (FBF-2), a PUF protein from the nematode Caenorhabditis elegans. FBF-2 plays a critical role in maintaining germline stem cell self-renewal.

Intramolecular Regulation

The authors found that FBF-2 contains an IDR at its C-terminus that autoinhibits its RNA-binding activity. This autoinhibition is mediated by an interaction between the IDR and the RBD. The IDR masks an electronegative cluster of amino acid residues on the RBD that is essential for RNA binding. Disrupting this interaction of the IDR or by deleting it results in increased RNA-binding affinity.

Intermolecular Regulation

The authors also showed that the FBF-2 C-terminal IDR interacts with Lateral Signaling Target-1 (LST-1), a partner protein that enhances FBF-2 RNA-binding activity. LST-1 binds to the same site on the RBD as the IDR, suggesting that it displaces the IDR and relieves autoinhibition. This mechanism allows LST-1 to modulate FBF-2 RNA-binding activity in response to cellular signals.

Implications for Germline Stem Cell Self-Renewal

The findings of this study provide a biochemical and biophysical explanation for the interdependence of FBF-2 and LST-1 in germline stem cell self-renewal. The dynamic regulation of FBF-2 RNA-binding activity by IDRs is likely critical for maintaining the proper balance between self-renewal and differentiation in germline stem cells.

Conclusion

This study highlights the importance of IDRs in regulating protein function, particularly in the context of RNA-binding proteins. The findings provide new insights into the mechanisms that control PUF protein RNA binding and their roles in cellular processes.

The findings of this study  challenge the traditional neo-Darwinian view that protein function is solely determined by its three-dimensional structure. 


Instead, they suggest that IDRs can play dynamic roles in regulating protein function through intramolecular interactions and interactions with partner proteins.

The study on FBF-2 regulation provides a compelling example of how IDRs can contribute to complex regulatory mechanisms and challenges the prevailing neo-Darwinian view of protein function. It suggests that IDRs are not mere structural fillers but rather dynamic functional elements that play critical roles in regulating protein-protein interactions and protein activity. Further research on the functional roles of IDRs in various biological contexts is likely to uncover new insights into the intricate mechanisms of cellular regulation.

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