Regulation of Biomolecular Condensates by Poly(ADP-ribose)

Rhine, Kevin; Odeh, Hana M.; Shorter, James; Myong, Sua

doi:10.1021/acs.chemrev.2c00851

Cited by 7 publications

(3 citation statements)

References 390 publications

(873 reference statements)

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“…Intriguingly, the TDP-43 NLS also harbors a poly(ADP-ribose) (PAR)-binding motif, which engages PAR. Thus, PAR may compete with importin-α for binding to the TDP-43 NLS, which may promote cytoplasmic mislocalization of TDP-43 under conditions where cytoplasmic PAR concentrations become elevated [ 6 , 69 – 71 ].…”

Section: Nuclear-transport Proteins Associate With Cargo Proteins And...mentioning

confidence: 99%

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Khalil,

Linsenmeier,

Smith

et al. 2024

Mol Neurodegeneration

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies. Graphical Abstract

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Section: Nuclear-transport Proteins Associate With Cargo Proteins And...mentioning

confidence: 99%

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Khalil,

Linsenmeier,

Smith

et al. 2024

Mol Neurodegeneration

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“…1B) [3][4][5][6][7] . PAR may also serve as a scaffold for protein complex or biomolecular condensate formation, where its negative charge allows for multivalent noncovalent interactions with basic proteins 8,9 .…”

Section: Introductionmentioning

confidence: 99%

Length-dependent Intramolecular Coil-to-Globule Transition in Poly(ADP-ribose) Induced by Cations

Wang,

Coshic,

Badiee

et al. 2023

Preprint

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Poly(ADP-ribose) (PAR), as part of a post-translational modification, serves as a flexible scaffold for noncovalent protein binding. Such binding is influenced by PAR chain length through a mechanism yet to be elucidated. Structural insights have been elusive, partly due to the difficulties associated with synthesizing PAR chains of defined lengths. Here, we employ an integrated approach combining molecular dynamics (MD) simulations with small-angle X-ray scattering (SAXS) experiments, enabling us to identify highly heterogeneous ensembles of PAR conformers at two different, physiologically relevant lengths: PAR15 and PAR22. Our findings reveal that numerous factors including backbone conformation, base stacking, and chain length contribute to determining the structural ensembles. We also observe length-dependent compaction of PAR upon the addition of small amounts of Mg2+ ions, with the 22-mer exhibiting ADP-ribose bundles formed through local intramolecular coil-to-globule transitions. This study illuminates how such bundling could be instrumental in deciphering the length-dependent action of PAR.

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“…Poly(ADP-ribose) polymerase-1 (PARP1) is a mammalian enzyme that ensures an essential function in maintaining genomic stability by regulating DNA repair and transcription [1]. The enzyme can be activated by binding to DNA with the structures of single-and double-strand breaks, hairpins, cruciforms or stably unpaired regions [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Streptavidin-Conjugated DNA for the Boronate Affinity-Based Detection of Poly(ADP-Ribose) Polymerase-1 with Improved Sensitivity

et al. 2023

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This work reports the development of a fluorescence method for the detection of poly(ADP-ribose) polymerase-1 (PARP1), in which a phenylboronic acid-modified fluorescein isothiocyanate dye (FITC-PBA) was used to recognize the formed poly(ADP-ribose) (PAR) polymer. The detection system was designed by conjugating recombinant streptavidin (rSA) with PARP1-specific double-stranded DNA (dsDNA) through streptavidin–biotin interaction. Capture of PARP1 via rSA–biotin–dsDNA allowed for the poly-ADP-ribosylation (PARylation) of both rSA and PARP1 in a homogeneous solution. The resulting rSA–biotin–dsDNA/PAR conjugates were then captured and separated via the commercialized nitrilotriacetic acid–nickel ion-modified magnetic bead (MB-NTA-Ni) through the interaction between NTA–Ni on MB surface and oligohistidine (His6) tag in rSA. The PAR polymer could capture the dye of FITC-PBA through the borate ester interaction between the boronic acid moiety in PBA and the cis-diol group in ribose, thus causing a decrease in fluorescence signal. The PARylation of streptavidin and the influence of steric hindrance on PARylation efficiency were confirmed using reasonable detection strategies. The method showed a wide linear range (0.01~20 U) and a low detection limit (0.01 U). This work should be valuable for the development of novel biosensors for the detection of poly(ADP-ribose) polymerases and diol-containing species.

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Regulation of Biomolecular Condensates by Poly(ADP-ribose)

Cited by 7 publications

References 390 publications

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Length-dependent Intramolecular Coil-to-Globule Transition in Poly(ADP-ribose) Induced by Cations

Streptavidin-Conjugated DNA for the Boronate Affinity-Based Detection of Poly(ADP-Ribose) Polymerase-1 with Improved Sensitivity

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