Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose)

Matthias Altmeyer; Kai J Neelsen; Federico Teloni; Irina Pozdnyakova; Stefania Pellegrino; Merete Grøfte; Maj-Britt Druedahl Rask; Werner Streicher; Stephanie Jungmichel; Michael Lund Nielsen; Jiri Lukas

doi:10.1038/ncomms9088

Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose)

Matthias Altmeyer, Kai J Neelsen, Federico Teloni, Irina Pozdnyakova, Stefania Pellegrino, Merete Grøfte, Maj-Britt Druedahl Rask, Werner Streicher, Stephanie Jungmichel, Michael Lund Nielsen, Jiri Lukas

Protein Production and Characterization Platform

230 Citationer (Scopus)

Abstract

Intrinsically disordered proteins can phase separate from the soluble intracellular space, and tend to aggregate under pathological conditions. The physiological functions and molecular triggers of liquid demixing by phase separation are not well understood. Here we show in vitro and in vivo that the nucleic acid-mimicking biopolymer poly(ADP-ribose) (PAR) nucleates intracellular liquid demixing. PAR levels are markedly induced at sites of DNA damage, and we provide evidence that PAR-seeded liquid demixing results in rapid, yet transient and fully reversible assembly of various intrinsically disordered proteins at DNA break sites. Demixing, which relies on electrostatic interactions between positively charged RGG repeats and negatively charged PAR, is amplified by aggregation-prone prion-like domains, and orchestrates the earliest cellular responses to DNA breakage. We propose that PAR-seeded liquid demixing is a general mechanism to dynamically reorganize the soluble nuclear space with implications for pathological protein aggregation caused by derailed phase separation.

Originalsprog	Engelsk
Artikelnummer	8088
Tidsskrift	Nature Communications
Vol/bind	6
Sider (fra-til)	1-12
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms9088
Status	Udgivet - 19 aug. 2015

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10.1038/ncomms9088

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abstract = "Intrinsically disordered proteins can phase separate from the soluble intracellular space, and tend to aggregate under pathological conditions. The physiological functions and molecular triggers of liquid demixing by phase separation are not well understood. Here we show in vitro and in vivo that the nucleic acid-mimicking biopolymer poly(ADP-ribose) (PAR) nucleates intracellular liquid demixing. PAR levels are markedly induced at sites of DNA damage, and we provide evidence that PAR-seeded liquid demixing results in rapid, yet transient and fully reversible assembly of various intrinsically disordered proteins at DNA break sites. Demixing, which relies on electrostatic interactions between positively charged RGG repeats and negatively charged PAR, is amplified by aggregation-prone prion-like domains, and orchestrates the earliest cellular responses to DNA breakage. We propose that PAR-seeded liquid demixing is a general mechanism to dynamically reorganize the soluble nuclear space with implications for pathological protein aggregation caused by derailed phase separation.",

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AU - Altmeyer, Matthias

AU - Neelsen, Kai J

AU - Teloni, Federico

AU - Pozdnyakova, Irina

AU - Pellegrino, Stefania

AU - Grøfte, Merete

AU - Rask, Maj-Britt Druedahl

AU - Streicher, Werner

AU - Jungmichel, Stephanie

AU - Nielsen, Michael Lund

AU - Lukas, Jiri

PY - 2015/8/19

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N2 - Intrinsically disordered proteins can phase separate from the soluble intracellular space, and tend to aggregate under pathological conditions. The physiological functions and molecular triggers of liquid demixing by phase separation are not well understood. Here we show in vitro and in vivo that the nucleic acid-mimicking biopolymer poly(ADP-ribose) (PAR) nucleates intracellular liquid demixing. PAR levels are markedly induced at sites of DNA damage, and we provide evidence that PAR-seeded liquid demixing results in rapid, yet transient and fully reversible assembly of various intrinsically disordered proteins at DNA break sites. Demixing, which relies on electrostatic interactions between positively charged RGG repeats and negatively charged PAR, is amplified by aggregation-prone prion-like domains, and orchestrates the earliest cellular responses to DNA breakage. We propose that PAR-seeded liquid demixing is a general mechanism to dynamically reorganize the soluble nuclear space with implications for pathological protein aggregation caused by derailed phase separation.

AB - Intrinsically disordered proteins can phase separate from the soluble intracellular space, and tend to aggregate under pathological conditions. The physiological functions and molecular triggers of liquid demixing by phase separation are not well understood. Here we show in vitro and in vivo that the nucleic acid-mimicking biopolymer poly(ADP-ribose) (PAR) nucleates intracellular liquid demixing. PAR levels are markedly induced at sites of DNA damage, and we provide evidence that PAR-seeded liquid demixing results in rapid, yet transient and fully reversible assembly of various intrinsically disordered proteins at DNA break sites. Demixing, which relies on electrostatic interactions between positively charged RGG repeats and negatively charged PAR, is amplified by aggregation-prone prion-like domains, and orchestrates the earliest cellular responses to DNA breakage. We propose that PAR-seeded liquid demixing is a general mechanism to dynamically reorganize the soluble nuclear space with implications for pathological protein aggregation caused by derailed phase separation.

U2 - 10.1038/ncomms9088

DO - 10.1038/ncomms9088

M3 - Journal article

C2 - 26286827

SN - 2041-1723

VL - 6

SP - 1

EP - 12

JO - Nature Communications

JF - Nature Communications

M1 - 8088

ER -

Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose)

Abstract

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