Mechanisms of self-assembly and fibrillization of the prion-like domains

Lu, Yaxin; L, Lim; Tan, Yi; Wang, Lin; Song, Jianxing

doi:10.1101/065631

Cited by 3 publications

(13 citation statements)

References 29 publications

(65 reference statements)

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“…2a, b). As such, these side chains are liberated and consequently available to form Bhydrogen bonds/polar/steric zippers^ (Lim et al 2016a;Lu et al 2016), as previously proposed for the amyloid fibrils formed by proteins enriched in Ser, Thr, Asn and Gln (Perutz et al 1994;Michelitsch and Weissman 2000;Nelson et al 2005;Han et al 2012).…”

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

confidence: 61%

“…By contrast, their formation of fibril structures with cross-β structures appeared to be much slower and highly pH-dependent, as monitored by the development of the intrinsic visible fluorescence and imaged by EM. Briefly, at pH 6.8, the formation of fibrils needed several days dependent on protein and salt concentrations, while at pH 4.0, no formation of fibrils has been observed for several months (Lim et al 2016a;Lu et al 2016). Furthermore, we have also characterized a truncated TDP-43 prion-like domain with only residues 342-414 which has a typical prion-like sequence enriched in polar and uncharged residues but lacking the middle hydrophobic region over region 311-341 (Lim et al 2016a;Lu et al 2016).…”

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

confidence: 98%

“…Surprisingly, despite being enriched in polar residues, the human prion-like domains appear to be intrinsically prone to aggregation to form amorphous structures at high concentrations of proteins and salts, as exemplified by the TDP-43 and FUS prion-like domains (Lim et al 2016a;Lu et al 2016Lu et al , 2017a. 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).…”

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). Furthermore, as indicated by low NMR temperature coefficients of most backbone amides, we found that, despite being intrinsically disordered, the TDP-43 prion-like domain contains a large number of intra-molecular hydrogen bonds between side chains of Ser, Thr, Asn, Gln and backbone atoms (I of Fig.…”

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

confidence: 99%

“…In particular, the exaggeration or molecular aging of liquid droplets into aggregation or amyloid fibrils may lie at the heart of a variety of human diseases including ALS (Murakami et al 2015;Patel et al 2015;Shin and Brangwynne 2017). The TDP-43 and FUS prion-like domains appear to remain highly disordered in the liquid droplets (Burke et al 2015;Lim et al 2016a;Conicella et al 2016;Lu et al 2016). Consequently, it remains poorly understood what is the driving force for LLPS.…”

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

confidence: 61%

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

confidence: 98%

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

confidence: 99%

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

confidence: 99%

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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RRM domain of ALS/FTD-causing FUS interacts with membrane: an anchor of membraneless organelles to membranes?

Lim

Song

2017

Preprint

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Abstract526-residue FUS functions to self-assemble into reversible droplets/hydrogels, which could be further solidified into pathological fibrils. FUS is composed of N-terminal low-sequence complexity (LC); RNA-recognition motif (RRM) and C-terminal LC domains. FUS belongs to an emerging category of proteins which are capable of forming membraneless organelles in cells via phase separation. On the other hand, eukaryotic cells contain a large network of internal membrane systems. Therefore, it is of fundamental importance to address whether membraneless organelles can interact with membranes. Here we attempted to explore this by NMR HSQC titrations of three FUS domains with gradual addition of DMPC/DHPC bicelle, which mimics the bilayer membrane. We found that both N- and C-terminal LC domains showed no significant interaction with bicelle, but its well-folded RRM domain does dynamically interact with bicelle with an interface opposite to that for binding nucleic acids including RNA and ssDNA. If this in vitro observation also occurs in cells, to interact with membrane might represent a mechanism for dynamically organizing membraneless organelles to membranes to facilitate their physiological functions.

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A Comprehensive Analysis of the Intrinsic Visible Fluorescence Emitted by Peptide/Protein Amyloid-like Assemblies

Balasco

Diaferia

Rosa

et al. 2023

IJMS

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Amyloid aggregation is a widespread process that involves proteins and peptides with different molecular complexity and amino acid composition. The structural motif (cross-β) underlying this supramolecular organization generates aggregates endowed with special mechanical and spectroscopic properties with huge implications in biomedical and technological fields, including emerging precision medicine. The puzzling ability of these assemblies to emit intrinsic and label-free fluorescence in regions of the electromagnetic spectrum, such as visible and even infrared, usually considered to be forbidden in the polypeptide chain, has attracted interest for its many implications in both basic and applied science. Despite the interest in this phenomenon, the physical basis of its origin is still poorly understood. To gain a global view of the available information on this phenomenon, we here provide an exhaustive survey of the current literature in which original data on this fluorescence have been reported. The emitting systems have been classified in terms of their molecular complexity, amino acid composition, and physical state. Information about the wavelength of the radiation used for the excitation as well as the emission range/peak has also been retrieved. The data collected here provide a picture of the complexity of this multifaceted phenomenon that could be helpful for future studies aimed at defining its structural and electronic basis and/or stimulating new applications.

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Mechanisms of self-assembly and fibrillization of the prion-like domains

Cited by 3 publications

References 29 publications

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

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

RRM domain of ALS/FTD-causing FUS interacts with membrane: an anchor of membraneless organelles to membranes?

A Comprehensive Analysis of the Intrinsic Visible Fluorescence Emitted by Peptide/Protein Amyloid-like Assemblies

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