A glass menagerie of low complexity sequences

Halfmann, Randal

doi:10.1016/j.sbi.2016.05.002

Cited by 33 publications

(37 citation statements)

References 72 publications

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“…The extent to which human amyloid-associated proteopathies likewise result from kinetically trapped non-amyloid assemblies remains to be tested. Nevertheless, our finding supports an emerging paradigm that non-amyloid assemblies contribute more to pathology than do amyloids (Halfmann, 2016;Knowles et al, 2014) .…”

Section: Condensate Metastability Underlies Proteopathic Aggregationsupporting

confidence: 77%

“…Ordered protein self assemblies function to transduce biological signals and encode molecular memories (Banani et al, 2017;Caudron and Barral, 2013;Chakrabortee et al, 2016;Halfmann, 2016;Si and Kandel, 2016;Wu and Fuxreiter, 2016) , but they also precipitate incurable degenerative diseases like Alzheimer's, Parkinson's, and ALS (reviewed in Knowles et al, 2014) . These phenomena emerge over much longer timescales than those typical either of protein folding or of liquid-liquid phase separation.…”

Section: Introductionmentioning

confidence: 99%

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Quantifying nucleationin vivoreveals the physical basis of prion-like phase behavior

Khan

Kandola

et al. 2017

Preprint

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Protein self-assemblies modulate protein activities over biological time scales that can exceed the lifetimes of the proteins or even the cells that harbor them. We hypothesized that these time scales relate to kinetic barriers inherent to the nucleation of ordered phases. To investigate nucleation barriers in living cells, we developed D istributed Am phifluoric FRET (DAmFRET). DAmFRET exploits a photoconvertible fluorophore, heterogeneous expression, and large cell numbers to quantify via flow cytometry the extent of a protein's self-assembly as a function of cellular concentration. We show that kinetic barriers limit the nucleation of ordered self-assemblies, and that the persistence of the barriers with respect to concentration relates to structure. Supersaturation resulting from sequence-encoded nucleation barriers gave rise to prion behavior, and enabled a prion-forming protein, Sup35 PrD, to partition into dynamic intracellular condensates or to form toxic aggregates. Our results suggest that nucleation barriers govern cytoplasmic inheritance, subcellular organization, and proteotoxicity.

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Section: Condensate Metastability Underlies Proteopathic Aggregationsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Quantifying nucleationin vivoreveals the physical basis of prion-like phase behavior

Khan

Kandola

et al. 2017

Preprint

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“…One hypothesis for the preponderance of disordered regions despite high amino acid sequence divergence, is that the "molecular features" of disordered regions that are important for function (such as length (Schlessinger et al, 2011), complexity Halfmann, 2016;Kato et al, 2012;Molliex et al, 2015), amino acid composition (Moesa et al, 2012), and net charge ) do not lead to detectable similarity in primary amino acid sequence alignments. Indeed, recently, evidence that such molecular features can be under evolutionary constraint has been reported for some proteins Lemas et al, 2016;.…”

Section: Introductionmentioning

confidence: 99%

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

Zarin

Strome

et al. 2019

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Intrinsically disordered regions make up a large part of the proteome, but the sequence-to-function relationship in these regions is poorly understood, in part because the primary amino acid sequences of these regions are poorly conserved in alignments. Here we use an evolutionary approach to detect molecular features that are preserved in the amino acid sequences of orthologous intrinsically disordered regions. We find that most disordered regions contain multiple molecular features that are preserved, and we define these as "evolutionary signatures" of disordered regions. We demonstrate that intrinsically disordered regions with similar evolutionary signatures can rescue function in vivo, and that groups of intrinsically disordered regions with similar evolutionary signatures are strongly enriched for functional annotations and phenotypes. We propose that evolutionary signatures can be used to predict function for many disordered regions from their amino acid sequences.

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“…Multivalent interactions among repetitive 58 protein-protein or protein-RNA interaction domains / motifs are the key determinants 59 of LLPS (Dennis, 2015; Fung et al, 2018). Multivalent contacts can be achieved with 60 tandem repeats of folded domains (Li et al, 2012), through low-complexity (LC) 61intrinsically disordered regions (IDRs) (Halfmann, 2016;Lin et al, 2015; Mittag and 62 Parker, 2018), or a combination of the two (Mitrea et al, 2016; Zhang et al, 2015). In 63 these systems, individual contacts are relatively weak.…”

mentioning

confidence: 99%

“…intrinsically disordered regions (IDRs) (Halfmann, 2016;Lin et al, 2015; Mittag and 62 Parker, 2018), or a combination of the two (Mitrea et al, 2016; Zhang et al, 2015). In 63 these systems, individual contacts are relatively weak.…”

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confidence: 99%

Arginine-enriched mixed-charge domains provide cohesion for nuclear speckle condensation

Greig

Nguyen

Lee

et al. 2019

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15Low-complexity protein domains promote the formation of various biomolecular 16condensates. However, in many cases, the precise sequence features governing 17 condensate formation and identity remain unclear. Here, we investigate the role of 18 intrinsically disordered mixed-charge domains (MCDs) in nuclear speckle 19 condensation. Proteins composed exclusively of arginine/aspartic-acid dipeptide 20 repeats undergo length-dependent condensation and speckle incorporation. 21Substituting arginine with lysine in synthetic and natural speckle-associated MCDs 22 abolishes these activities, identifying a key role for multivalent contacts through 23 arginine's guanidinium ion. MCDs can synergise with a speckle-associated RNA 24 recognition motif to promote speckle specificity and residence. MCD behaviour is 25 tuneable through net-charge: increasing negative charge abolishes condensation and 26 speckle incorporation. By contrast, increasing positive charge through arginine leads 27 to enhanced condensation, speckle enlargement, decreased splicing factor mobility, 28 and defective mRNA export. Together, these results identify key sequence 29 determinants of MCD-promoted speckle condensation, and link the speckle's dynamic 30 material properties with function in mRNA processing. 31 32 33 34 2015; Nott et al., 2015; Patel et al., 2015). Multivalent interactions among repetitive 58 protein-protein or protein-RNA interaction domains / motifs are the key determinants 59 of LLPS (Dennis, 2015; Fung et al., 2018). Multivalent contacts can be achieved with 60 tandem repeats of folded domains (Li et al., 2012), through low-complexity (LC) 61intrinsically disordered regions (IDRs) (Halfmann, 2016;Lin et al., 2015; Mittag and 62 Parker, 2018), or a combination of the two (Mitrea et al., 2016; Zhang et al., 2015). In 63 these systems, individual contacts are relatively weak. However, with increasing 64 valence, the combined effect of many weak interactions overcome the entropic cost of 65 (Hyman et al., 2014). In many cases LC-IDRs have been shown to be necessary 66 and sufficient for LLPS. This raises key questions regarding the types of residues that 67 promote intermolecular contacts, and the extent to which these determine condensate 68 LLPSResults 103 104 Mixed-charge domains (MCDs) undergo condensation and localize to nuclear 105 speckles 106We previously showed that an arginine and aspartic acid (RD)-enriched MCD 107 from the fungal SPA-5 (SPA-5 MCD ) protein forms a viscoelastic hydrogel. In the fungus, 108 this activity is associated with the formation of cytoplasmic plugs that gate cell-to-cell 109 channels (Lai et al., 2012). To explore the role of such sequences in animal cells, we 110 expressed SPA-5 MCD as an mGFP-fusion in HeLa cells (SPA-5 MCD -mGFP). In this 111 context, SPA-5 MCD -mGFP accumulates in nuclear speckles as revealed by co-112 localization with the speckle marker serine/arginine-rich splicing factor 1 (SRSF1) 113( Figures 1A and S1A). SPA-5 MCD is enriched in RD dipeptide repeats. However, it als...

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A glass menagerie of low complexity sequences

Cited by 33 publications

References 72 publications

Quantifying nucleationin vivoreveals the physical basis of prion-like phase behavior

Quantifying nucleationin vivoreveals the physical basis of prion-like phase behavior

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

Arginine-enriched mixed-charge domains provide cohesion for nuclear speckle condensation

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