Structure of FUS Protein Fibrils and Its Relevance to Self-Assembly and Phase Separation of Low-Complexity Domains

Murray, Dylan T.; Kato, Masato; Lin, Yen‐Chu; Thurber, Kent R.; Hung, Ivan; McKnight, Steven L.; Tycko, Robert

doi:10.1016/j.cell.2017.08.048

Cited by 675 publications

(946 citation statements)

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“…Phosphorylation and other modifications likewise provide a means of adjusting droplet composition; many of these events modulate the inclusion (or exclusion) of different components (Fig. 1), such as FUS 45 and RNA polymerase in stress granules 46 .…”

Section: Regulating Phase Separationmentioning

confidence: 99%

It Pays To Be in Phase

2018

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To survive, organisms must orchestrate many competing biochemical and regulatory processes in time and space. Recent work has suggested that the underlying chemical properties of some biomolecules allow them to self-organize, and that life may have exploited this property to organize biochemistry in space and time within cells. Such phase separation is ubiquitous, particularly among the many regulatory proteins that harbor prion-like intrinsically disordered domains. And yet, despite evident regulation by post-translational modification and myriad other stimuli, the biological significance of many phase-separated compartments remains uncertain. Many potential functions have been proposed but far fewer have been demonstrated. A burgeoning subfield at the intersection of cell biology and polymer physics has defined the biophysical underpinnings that govern the genesis and stability of these particles. The picture is complex: many assemblies are composed of multiple proteins that each have the capacity to phase separate. Here, we briefly discuss this foundational work and survey recent efforts combining targeted biochemical perturbations and quantitative modeling to specifically address the diverse roles that phase separation processes may play in biology.

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Section: Regulating Phase Separationmentioning

confidence: 99%

It Pays To Be in Phase

2018

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“…Very recently, the structure of the dynamic fibril of the FUS prion-like domain over residues 39-95 has been successfully determined by solid-state NMR spectroscopy (Murray et al 2017), which is almost completely constrained by interactions involved in polar (Ser, Thr, Asn and Gln) and aromatic (Tyr) residues (I of Fig. 2c).…”

Section: Aggregation and Self-assembly Into Liquid Droplets And Fibrimentioning

confidence: 99%

“…On the other hand, under some conditions, like the yeast prion proteins (Shorter and Lindquist 2005;Michelitsch and Weissman 2000;Chien and Weissman 2001), the TDP-43 and FUS prion-like domains have been biophysically characterized to form fibril/hydrogel structures with cross-β structures (Han et al 2012;Lim et al 2016a;Lu et al 2016;Kato and McKnight 2017;Murray et al 2017). Very unexpectedly, we discovered that the self-assembly of both TDP-43 and FUS prion-like domains into the fibril structures is highly pHdependent (Lim et al 2016a;Lu et al 2016): at low pH such as 4.0, they remained mostly monomeric for many weeks, while at neutral pH they showed a strong capacity to selfassemble into fibrils with cross-β structures as reflected by the development of intrinsic visible fluorescence, which is a novel protein fluorescence originating from the hydrogenbonding network in β-rich secondary structures (Shukla et al 2004;Chan et al 2013;Lim et al 2016a;Lu et al 2016;Pinotsi et al 2016).…”

Section: Aggregation and Self-assembly Into Liquid Droplets And Fibrimentioning

confidence: 99%

“…Most amazingly, this mechanism offers the potential to generate conformational ensembles composed of enormous amounts of states for both liquid droplets and fibril structures, which are also extremely sensitive to various environmental factors such as pH and cellular processes, including phosphorylation of Ser, Thr and Tyr (Murray et al 2017;Monahan et al 2017;Shorter 2017). Therefore, it appears most likely that the biological functions of the prion-like domains request not just the formation of the liquid droplets but also the conformational dynamics, as well as further assembly into diverse fibril structures.…”

Section: Aggregation and Self-assembly Into Liquid Droplets And Fibrimentioning

confidence: 99%

“…Consequently, it remains poorly understood what is the driving force for LLPS. Furthermore, the relationship between the formation of liquid droplets and fibrils/hydrogels is highly controversial (Han et al 2012;Burke et al 2015;Conicella et al 2016;Kato and McKnight 2017;Murray et al 2017).…”

Section: Aggregation and Self-assembly Into Liquid Droplets And Fibrimentioning

confidence: 99%

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Environment-transformable sequence–structure relationship: a general mechanism for proteotoxicity

Song

2017

Biophys Rev

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In his Nobel Lecture, Anfinsen stated Bthe native conformation is determined by the totality of interatomic interactions and hence by the amino acid sequence, in a given environment.^As aqueous solutions and membrane systems co-exist in cells, proteins are classified into membrane and non-membrane proteins, but whether one can transform one into the other remains unknown. Intriguingly, many well-folded non-membrane proteins are converted into Binsoluble^and toxic forms by aging-or diseaseassociated factors, but the underlying mechanisms remain elusive. In 2005, we discovered a previously unknown regime of proteins seemingly inconsistent with the classic BSalting-in^dogma: Binsoluble^proteins including the integral membrane fragments could be solubilized in the ion-minimized water. We have thus successfully studied Binsoluble^forms of ALScausing P56S-MSP, L126Z-SOD1, nascent SOD1 and C71G-Profilin1, as well as E. coli S1 fragments. The results revealed that these Binsoluble^forms are either unfolded or co-exist with their unfolded states. Most unexpectedly, these unfolded states acquire a novel capacity of interacting with membranes energetically driven by the formation of helices/loops over amphiphilic/ hydrophobic regions which universally exit in proteins but are normally locked away in their folded native states. Our studies suggest that most, if not all, proteins contain segments which have the dual ability to fold into distinctive structures in aqueous and membrane environments. The abnormal membrane interaction might initiate disease and/or aging processes; and its further coupling with protein aggregation could result in radical proteotoxicity by forming inclusions composed of damaged membranous organelles and protein aggregates. Therefore, environment-transformable sequence-structure relationship may represent a general mechanism for proteotoxicity.

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Biological functions, regulatory mechanisms, and disease relevance of RNA localization pathways

et al. 2018

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The asymmetric subcellular distribution of RNA molecules from their sites of transcription to specific compartments of the cell is an important aspect of post-transcriptional gene regulation. This involves the interplay of intrinsic cis-regulatory elements within the RNA molecules with trans-acting RNAbinding proteins and associated factors. Together, these interactions dictate the intracellular localization route of RNAs, whose downstream impacts have wide-ranging implications in cellular physiology. In this review, we examine the mechanisms underlying RNA localization and discuss their biological significance. We also review the growing body of evidence pointing to aberrant RNA localization pathways in the development and progression of diseases.Keywords: Cis-regulatory elements; RNA disease; RNA localization; RNA-binding proteinsThe asymmetric organization of cells is a pervasive feature that ensures the homeostasis of prokaryotic and eukaryotic organisms. This relies on the capacity of cells to organize their contents, including lipids, nucleic acids, and proteins, into specific subcellular structures and organelles. While much of this organization has been attributed to subcellular protein transport [1], a growing body of work indicates that the regulated localization of RNA molecules is also a key process observed across evolutionary timescales [2][3][4][5][6]. This form of post-transcriptional regulation where coding and noncoding RNA molecules actively associate with trans-acting partners, such as RNA-binding proteins (RBPs), serves to dictate both the function and intra-or extracellular destiny of the RNA. During RNA localization, cis-regulatory elements found within the RNA molecule, whether coding or noncoding, act as recognition sites for the recruitment of trans-acting RBPs, which dictate the intra-/extra-cellular fate of the RNA and, ultimately, its functional state. Over the years, the wide-ranging implications of RNA localization on cellular physiology have become apparent, affecting many aspects of cell organization and function. Indeed, RNA localization pathways have been linked to numerous important processes, including developmental patterning, cell polarity, spindle assembly, formation of nonmembranous compartments, localized translation, and cell motility [2][3][4][5][6].

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Structure of FUS Protein Fibrils and Its Relevance to Self-Assembly and Phase Separation of Low-Complexity Domains

Cited by 675 publications

References 70 publications

It Pays To Be in Phase

It Pays To Be in Phase

Environment-transformable sequence–structure relationship: a general mechanism for proteotoxicity

Biological functions, regulatory mechanisms, and disease relevance of RNA localization pathways

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