Interactions between the Intrinsically Disordered Regions of hnRNP-A2 and TDP-43 Accelerate TDP-43′s Conformational Transition

Abstract

Most biological functions involve protein–protein interactions. Our understanding of these interactions is based mainly on those of structured proteins, because encounters between intrinsically disordered proteins (IDPs) or proteins with intrinsically disordered regions (IDRs) are much less studied, regardless of the fact that more than half eukaryotic proteins contain IDRs. RNA-binding proteins (RBPs) are a large family whose members almost all have IDRs in addition to RNA binding domains. These IDRs, having low sequence similarity, interact, but structural details on these interactions are still lacking. Here, using the IDRs of two RBPs (hnRNA-A2 and TDP-43) as a model, we demonstrate that the rate at which TDP-43′s IDR undergoes the neurodegenerative disease related α-helix-to-β-sheet transition increases in relation to the amount of hnRNP-A2′s IDR that is present. There are more than 1500 RBPs in human cells and most of them have IDRs. RBPs often join the same complexes to regulate genes. In addition to the structured RNA-recognition motifs, our study demonstrates a general mechanism through which RBPs may regulate each other’s functions through their IDRs.

Metals in ALS TDP-43 Pathology

“…The hydrophobicity values were calculated using the ProtScale software [102] and parameters provided by Abraham and Leo, 1987 [103]. The C-terminal domain (Figure 2) is glycine-rich and mainly disordered [104], and several ALS-related mutations are located there [100]. The N-terminal domain (Figure 2) contains six beta-strands and one alpha helix [105] and is followed by two tandem RNA recognition motifs-RRM1 and RRM2, collectively referred to as RRM1/2-that are highly conserved and important for binding nucleic acids [28,106].…”

Neurotrophic Viruses in the Pathogenesis of ALS

“…Subsequent studies confirmed that hyperphosphorylated TDP-43 impairs small interfering RNA silencing, which is the major post-transcriptional mechanism of retrotransposable elements or genomic parasites as a novel mechanism of neurodegeneration in ALS [14]. TDP-43 has been shown to contain a prion-like domain that can form a self-replicating amyloid conformation [15] TDP-43 possesses intrinsically disordered domains whereby the rate αhelix-to-β-sheet transition is dependent upon post translational modifications of phosphorylationdephosphorylation pathways [16]. Furthermore, prion-like domains may directly originate during viral genomic RNA processing involving nucleocapsid (NC) proteins responsible for virus capsid assembly and structure [17].…”

RNA-Binding Proteins as Epigenetic Regulators of Brain Functions and Their Involvement in Neurodegeneration

“…Notably, while studying the interaction between HnRNP-A2 and TDP-43, a mechanism of reciprocal regulation through IDRs was evidenced: in some neurodegenerative diseases (see Section 4 ), TDP-43 shows a transition from an alfa-helix to a beta-sheet structure, which favors its aggregation, and it was found that an increase in the disordered conformation of HnRNP-A2 is directly related to the increase in the beta-sheet structure in TDP-43 [ 154 ]. Such a kind of interaction, based on IDRs, is probably responsible for the aggregation-dependent alterations noticed in most neurodegenerative diseases.…”