Abstract
The visible outcome of liquid-liquid phase transitions (LLPTs) in cells is the formation and disintegration of various proteinaceous membrane-less organelles (PMLOs). Although LLPTs and related PMLOs have been observed in living cells for over 200 years, the physiological functions of these transitions (also known as liquid-liquid phase separation, LLPS) are just starting to be understood. While unveiling the functionality of these transitions is important, they have come into light more recently due to the association of abnormal LLPTs with various pathological conditions. In fact, several maladies, such as various cancers, different neurodegenerative diseases, and cardiovascular diseases, are known to be associated with either aberrant LLPTs or some pathological transformations within the resultant PMLOs. Here, we will highlight both the physiological functions of cellular liquid-liquid phase transitions as well as the pathological consequences produced through both dysregulated biogenesis of PMLOs and the loss of their dynamics. We will also discuss the potential downstream toxic effects of proteins that are involved in pathological formations.
Highlights
Examples of systems undergoing dynamic liquid-gel phase separation (LGPS) include heterotypic polymerization of the low complexity domains (LCDs) of the fused in sarcoma (FUS) RNA-binding protein with RNA [119]; polymerization of mutant FUS forms associated with amyotrophic lateral sclerosis (ALS) [121]; RNA-dependent hydrogel formation of the LCDs of CIRBP, RBM3, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), hnRNPA2, yeast Sup35 protein [119,122], Ewings sarcoma (EWS), and TATA-binding protein-associated factor 15 (TAF15) proteins [120]; and FG-rich repeat regions of some nucleoporins, such as yeast nucleoporin Nsp1p [118]
Since post-translational modifications (PTMs) represent one of the sides of “biological dark matter”, and since many PTMs occur in intrinsically disordered protein regions (IDPRs), it was indicated that such disorder-centered PTMs constitute the darker side of the biological dark matter [139]
In addition to numerous physiological roles of PARylation that range from gene expression to DNA repair, mitochondrial biogenesis, neuroinflammation, and regulation of a variety of signaling pathways inducing different forms of cell death, alterations in this PTM were associated with aberrant liquid-liquid phase transitions (LLPTs) and pathological aggregation of several proteins, such as α-synuclein, TDP-43, and heterogeneous nuclear ribonucleoprotein A1 [146] associated with Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington disease (HD), and amyotrophic lateral sclerosis (ALS)
Summary
There are no doubts that many biological functions do not require unique protein structures. Different parts of a protein molecule can be under-folded to different degrees This defines an astonishing multi-level spatiotemporal heterogeneity of IDP/IDPR, whose mosaic structure represents a complex combination of foldons (independently foldable units), inducible foldons (disordered regions that can (partially) fold at interaction with the binding partners), morphing inducible foldons (disordered regions that can differently fold at interaction with different binding partners), non-foldons (non-foldable protein regions), semi-foldons (regions that are always in a semi-folded form), and unfoldons (ordered regions that have to undergo an order-to-disorder transition to become functional) [21,26,27,28,29]. IDPs/IDPRs lack the hydrophobic cores typical for ordered proteins and do not have unique 3-D-structures, many of them are not completely structure-less random coils, but have some local preferences for transient secondary structure elements and even for some transient tertiary contacts Such dynamic pre-organization imposes spatial restrictions on IDPs, exposing some of their potential contact sites. IDPs and hybrid proteins with IDPRs can be compartmentalized within a cell, being responsible for the biogenesis of different proteinaceous membrane-less organelles (PMLOs) [52,53,54,55,56], which represent a crucial illustration of the emergent behavior of IDPs/IDPRs related to their “edge of chaos” character
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