Poly(ADP-ribose): A Dynamic Trigger for Biomolecular Condensate Formation - PubMed (original) (raw)

Review

Poly(ADP-ribose): A Dynamic Trigger for Biomolecular Condensate Formation

Anthony K L Leung. Trends Cell Biol. 2020 May.

Abstract

Poly(ADP-ribose) (PAR) is a nucleic acid-like protein modification that can seed the formation of microscopically visible cellular compartments that lack enveloping membranes, recently termed biomolecular condensates. These PAR-mediated condensates are linked to cancer, viral infection, and neurodegeneration. Recent data have shown the therapeutic potential of modulating PAR conjugation (PARylation): PAR polymerase (PARP) inhibitors can modulate the formation and dynamics of these condensates as well as the trafficking of their components - many of which are key disease factors. However, the way in which PARylation facilitates these functions remains unclear, partly because of our lack of understanding of the fundamental parameters of intracellular PARylation, including the sites that are conjugated, PAR chain length and structure, and the physicochemical properties of the conjugates. This review first introduces the role of PARylation in regulating biomolecular condensates, followed by discussion of current knowledge gaps, potential solutions, and therapeutic applications.

Keywords: ADP-ribosylation; biomolecular condensate; liquid–liquid phase separation; poly(ADP-ribose); poly(ADP-ribose) polymerase; poly(ADP-ribose) polymerase inhibitor.

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Figures

Fig. 1 |. Poly(ADP-ribose) code (varying sites, length and structure) directs protein interactions within biomolecular condensates.

(A) PAR can be conjugated to different amino acids with varying numbers of ADP-ribose (blue pentagon) and the ADP-ribose can be connected with two possible configurations, resulting in linear and branched chain formation. Analogous to the ubiquitin code, the varying site, length and structure may comprise a PAR code directing biological outcomes. (B) Multivalency can be achieved by multiple PARylated sites from a single protein or by a PAR chain comprising multiple ADP-ribose units for binding to proteins (magenta). Recent data also indicate that the length and structure of PAR are determinants of protein binding (e.g., orange proteins in the illustration require the binding of three ADP-ribose units whereas the red protein binds to the branchpoint of PAR. Therefore, the formation of different PAR may increase the number of multivalent interactions critical for phase separation. (C) PAR can serve a scaffold, where its length and structure specify which client proteins to recruit, resulting in compositional control of biomolecular condensates.

Figure I |

ADP-ribosylation Dynamics

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Poly(ADP-ribose): A Dynamic Trigger for Biomolecular Condensate Formation - PubMed (original) (raw)