Intrinsically Disordered Regions Can Contribute Promiscuous Interactions to RNP Granule Assembly

Abstract

SUMMARY Eukaryotic cells contain large RNA-protein assemblies referred to as RNP granules, whose assembly is promoted by both traditional protein interactions and intrinsically disordered protein domains. Using RNP granules as an example, we provide evidence for an assembly mechanism of large cellular structures wherein specific protein-protein or protein-RNA interactions act together with promiscuous interactions of intrinsically disordered regions (IDRs). This synergistic assembly mechanism illuminates RNP granule assembly and explains why many components of RNP granules, and other large dynamic assemblies, contain IDRs linked to specific protein-protein or protein-RNA interaction modules. We suggest assemblies based on combinations of specific interactions and promiscuous IDRs are common features of eukaryotic cells.

Proteome-wide signatures of function in highly diverged intrinsically disordered regions

“…Another interesting example is cluster O, which contains IDRs from proteins that are enriched for a wide range of annotations such as "P-body", "cytoplasmic stress granule", "actin cortical patch", and "DNA binding". Cluster O contains IDRs from proteins associated with phase separation and membraneless organelles such as Sup35 (Franzmann et al, 2018) and Dhh1 (Protter et al, 2018). The evolutionary signatures for the IDRs in this cluster include features that are typically associated with so-called "prionogenic", low complexity disordered regions, such as increased mean polyglutamine repeats ), but also indicate that there are other relevant molecular features for this set of disordered regions (Fig.…”

RNAs, Phase Separation, and Membrane‐Less Organelles: Are Post‐Transcriptional Modifications Modulating Organelle Dynamics?

“…Proteins prone to undergoing LLPS are either multi‐domain proteins or harbor intrinsically disordered regions (IDRs), often also referred to as prion‐like domains (PLDs) . Individual IDRs can self‐associate and form oligomeric structures through multiple weak and adhesive interactions such as cation‐pi, pi‐stacking, or dipolar interactions between stretches of particular “disorder‐promoting” amino acids (i.e., Q, S, N, Y, G), all resulting in phase separation of interacting proteins from surrounding solution . The ensuing multi‐valency governs inter‐ and intramolecular interactions resulting in the assembly of oligo‐ and polymeric structures in which valency (the number of interaction modules) and affinity (strength of interactions of individual modules) are the key parameters controlling LLPS.…”

RNA promotes phase separation of glycolysis enzymes into yeast G bodies in hypoxia

“…G body recruitment requires multivalent interactions. IDRs have been shown to modify phase separation behavior in vitro and in vivo (Kato et al, 2012;Mitrea & Kriwacki, 2016;Molliex et al, 2015;Protter et al, 2018). Pfk2 has such an IDR in its N-terminal domain ( Fig 5A).…”

“…Many other phase-separated structures contain RNA. For instance, stress granules contain mRNAs stalled in translation initiation (Buchan, Muhlrad, & Parker, 2008) and involve protein-protein and IDR interactions between mRNA binding proteins (Panas, Ivanov, & Anderson, 2016;Protter et al, 2018). Nucleoli, which are sites of ribosomal RNA processing, also form by phase separation (Brangwynne, Mitchison, & Hyman, 2011;Protter et al, 2018).…”