Dynamic structural order of a low-complexity domain facilitates assembly of intermediate filaments

Sysoev, Vasiliy O.; Kato, Masato; Sutherland, Lillian B.; Hu, Renzhi; McKnight, Steven L.; Murray, Dylan T.

doi:10.1073/pnas.2010000117

Cited by 25 publications

(30 citation statements)

References 38 publications

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“…This type of dynamically structured LC domain is not unprecedented, as we have recently observed such a phenomena in a LC domain of intermediate filament protein assemblies. 43 These data all reinforce our interpretation that delicately balanced interactions determine the functional and pathological assembly of TDP-43-LC.…”

Section: Tdp-43-lc Domain Interactions In the Full-length Proteinsupporting

confidence: 69%

Identification of the Rigid Core for Aged Liquid Droplets of the TDP-43 Low Complexity Domain

Bd¹,

Km²,

Nr³

et al. 2021

Preprint

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The biomolecular condensation of proteins with low complexity sequences plays a functional role in RNA metabolism and a pathogenic role in neurodegenerative diseases. The formation of dynamic liquid droplets brings biomolecules together to achieve complex cellular functions. The rigidification of liquid droplets into β-strand-rich hydrogel structures composed of protein fibrils is thought to be purely pathological in nature. However, low complexity sequences often harbor multiple fibril-prone regions with delicately balanced functional and pathological interactions. Here, we investigate the maturation of liquid droplets formed by the low complexity domain of the TAR DNA-binding protein 43 (TDP-43). Solid state nuclear magnetic resonance measurements on the aged liquid droplets identify a structured core region distinct from the region thought to be most important for pathological fibril formation and aggregation. The results of this study show that multiple segments of this low complexity domain are prone to form fibrils, and that stabilization of β-strand-rich structure in one segment precludes the other region from adopting rigid fibril structure.

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Section: Tdp-43-lc Domain Interactions In the Full-length Proteinsupporting

confidence: 69%

Identification of the Rigid Core for Aged Liquid Droplets of the TDP-43 Low Complexity Domain

Bd¹,

Km²,

Nr³

et al. 2021

Preprint

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“…28 The procedure used is similar to our work on other LC domain proteins. [29][30][31][32] A complete description of the assignment calculations is presented in the Methods section. Signals representing an amino acid sequence of XGXX (consistent with residues W309-W312 or I319-Y322) could not be unambiguously assigned due to the low signal to noise of the flanking residues, suggesting an ordered region surrounded by more mobile segments of the protein.…”

Section: Residues A338-n357 Of the Tia1 Lc Domain Form β-Strand Rich ...mentioning

confidence: 99%

“…Reducing the temperature probes the presence of loosely ordered but conformationally homogenous structure in these samples. 30 As molecular motions decrease with temperature, cross polarization and TEDOR based magnetization transfers should be more efficient due to stronger dipolar coupling interactions. Notably, the signals reporting on the seeded wild-type fibril conformation do not appear in these spectra.…”

Section: Wild-type and P362l Mutant Tia1 Lc Domain Aged Droplets Are ...mentioning

confidence: 99%

Liquid droplet aging and fibril formation of the stress granule protein TIA1 low complexity domain

Wittmer

Jami

Stowell

et al. 2022

Preprint

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Protein domains biased toward a few amino acid types are vital for the formation of biomolecular condensates in living cells. These membraneless compartments are formed by molecules exhibiting a range of molecular motions and structural order. Missense mutations increase condensate persistence lifetimes or structural order, properties that are thought to underlie pathological protein aggregation. We examined seeded fibrils of the T-cell restricted intracellular antigen-1 low complexity domain and determined residues 338-357 compose the rigid fibril core. Aging of wild-type and P362L mutant low complexity domain liquid droplets resulted in fibril assemblies that are structurally distinct from the seeded fibril preparation. The results show that most disease mutations lie outside the region that forms homogeneous fibril structure, the droplets age into conformationally heterogenous fibrils, and the P362L disease mutation does not favor a specific fibril conformation.

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“…Intrinsically disordered proteins (IDPs) are abundantly present in nature and play important roles in diverse biological functions, including cellular signaling and regulation of gene expression. 1 − 8 A class of IDPs, defined as low complexity domains (LCDs), have been recently discovered in association with the dynamic formation of open compartments in cells. 4 − 8 These compartments, which are often defined as condensates, are associated with liquid–liquid phase separation (LLPS) of proteins and nucleic acids and could underlie important functions and dysfunctions in biology.…”

Section: Introductionmentioning

confidence: 99%

Modeling the Structure and Interactions of Intrinsically Disordered Peptides with Multiple Replica, Metadynamics-Based Sampling Methods and Force-Field Combinations

Casalini

Arosio

et al. 2022

J. Chem. Theory Comput.

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Intrinsically disordered proteins play a key role in many biological processes, including the formation of biomolecular condensates within cells. A detailed characterization of their configurational ensemble and structure–function paradigm is crucial for understanding their biological activity and for exploiting them as building blocks in material sciences. In this work, we incorporate bias-exchange metadynamics and parallel-tempering well-tempered metadynamics with CHARMM36m and CHARMM22* to explore the structural and thermodynamic characteristics of a short archetypal disordered sequence derived from a DEAD-box protein. The conformational landscapes emerging from our simulations are largely congruent across methods and force fields. Nevertheless, differences in fine details emerge from varying combinations of force-fields and sampling methods. For this protein, our analysis identifies features that help to explain the low propensity of this sequence to undergo self-association in vitro, which are common to all force-field/sampling method combinations. Overall, our work demonstrates the importance of using multiple force-field and sampling method combinations for accurate structural and thermodynamic information in the study of disordered proteins.

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Dynamic structural order of a low-complexity domain facilitates assembly of intermediate filaments

Cited by 25 publications

References 38 publications

Identification of the Rigid Core for Aged Liquid Droplets of the TDP-43 Low Complexity Domain

Identification of the Rigid Core for Aged Liquid Droplets of the TDP-43 Low Complexity Domain

Liquid droplet aging and fibril formation of the stress granule protein TIA1 low complexity domain

Modeling the Structure and Interactions of Intrinsically Disordered Peptides with Multiple Replica, Metadynamics-Based Sampling Methods and Force-Field Combinations

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