Download MendeleyPARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain.
Dawicki-McKenna, J.M., Langelier, M.F., DeNizio, J.E., Riccio, A.A., Cao, C.D., Karch, K.R., McCauley, M., Steffen, J.D., Black, B.E., Pascal, J.M.(2015) Mol Cell 60: 755-768
- PubMed: 26626480
- DOI: https://doi.org/10.1016/j.molcel.2015.10.013
- Primary Citation of Related Structures:
5DS3, 5DSY - PubMed Abstract:
Poly(ADP-ribose) polymerase-1 (PARP-1) creates the posttranslational modification PAR from substrate NAD(+) to regulate multiple cellular processes. DNA breaks sharply elevate PARP-1 catalytic activity to mount a cell survival repair response, whereas persistent PARP-1 hyperactivation during severe genotoxic stress is associated with cell death. The mechanism for tight control of the robust catalytic potential of PARP-1 remains unclear. By monitoring PARP-1 dynamics using hydrogen/deuterium exchange-mass spectrometry (HXMS), we unexpectedly find that a specific portion of the helical subdomain (HD) of the catalytic domain rapidly unfolds when PARP-1 encounters a DNA break. Together with biochemical and crystallographic analysis of HD deletion mutants, we show that the HD is an autoinhibitory domain that blocks productive NAD(+) binding. Our molecular model explains how PARP-1 DNA damage detection leads to local unfolding of the HD that relieves autoinhibition, and has important implications for the design of PARP inhibitors.
Organizational Affiliation:
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6059, USA.
