Cation-induced intramolecular coil-to-globule transition in poly(ADP-ribose)
Poly(ADP-ribose) (PAR), a non-canonical nucleic acid, is essential for DNA/RNA metabolism and protein condensation, and its dysregulation is linked to cancer and neurodegeneration. However, key structural insights into PAR's functions remain largely uncharacterized, hindered by the challenges in synthesizing and characterizing PAR, which are attributed to its length heterogeneity. A central issue is how PAR, comprised solely of ADP-ribose units, attains specificity in its binding and condensing proteins based on chain length. Here, we integrate molecular dynamics simulations with small-angle X-ray scattering to analyze PAR structures. We identify diverse structural ensembles of PAR that fall into distinct subclasses and reveal distinct compaction of two different lengths of PAR upon the addition of small amounts of Mg<sup>2+</sup> ions. Unlike PAR<sub>15</sub>, PAR<sub>22</sub> forms ADP-ribose bundles via local intramolecular coil-to-globule transitions. Understanding these length-dependent structural changes could be central to deciphering the specific biological functions of PAR.
Authors
- Lois Pollack (ORCID: https://orcid.org/0000-0002-9366-4396)
- Anthony K. L. Leung (ORCID: https://orcid.org/0000-0001-5569-4036)
- Kush Coshic (ORCID: https://orcid.org/0000-0002-7179-4624)
- Mohsen Badiee (ORCID: https://orcid.org/0000-0003-3722-4609)
- Tong Wang (ORCID: https://orcid.org/0000-0002-7569-6386)
- Aleksei Aksimentiev (ORCID: https://orcid.org/0000-0002-6042-8442)
- Maranda R McDonald
Institutions
- Johns Hopkins University (US)
- University of Illinois Urbana-Champaign (US)
- Cornell University (US)
- Johns Hopkins Medicine (US)
- University of Baltimore (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-10
- DOI
- https://doi.org/10.1038/s41467-024-51972-9
- Citations
- 10
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 2.83
Funders
- National Science Foundation
- U.S. Department of Energy
- Empire State Development Corporation
- Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada
- National Institutes of Health
- Natural Sciences and Engineering Research Council of Canada
- National Institute of General Medical Sciences
- Division of Materials Research
- Biological and Environmental Research
- Brookhaven National Laboratory