PXD043794-2

PXD043794 is an original dataset announced via ProteomeXchange.

Title	A PARP2 active site α-helix melts to permit DNA damage-induced enzymatic activation
Description	PARP1 and PARP2 recognize DNA breaks immediately upon their formation, generate a burst of local PARylation to signal their location, and are co-targeted by all current FDA-approved forms of PARP inhibitors (PARPi) used in the cancer clinic. Recent evidence indicates that the same PARPi molecules impact PARP2 differently from PARP1, raising the possibility that allosteric activation may also differ. We find that unlike for PARP1, destabilization of the autoinhibitory domain of PARP2 is insufficient for DNA damage-induced catalytic activation. Rather, PARP2 activation requires further unfolding of an active site α-helix. In contrast, the corresponding α-helix in PARP1 only transiently forms, even prior to engaging DNA. Only one clinical PARPi, Olaparib, stabilizes the PARP2 active site α-helix, representing a structural feature with the potential to discriminate small molecule inhibitors. Collectively, our findings reveal unanticipated differences in local structure and changes in activation-coupled backbone dynamics between PARP1 and PARP2.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_07:00:04.414.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Emily Smith
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-14 12:36:42	ID requested
1	2024-09-30 06:06:35	announced
⏵ 2	2024-10-22 07:00:04	announced	2024-10-22: Updated project metadata.

10.1101/2024.05.20.594972;

submitter keyword: PARP2, PARPi, HDX-MS, active site loop

Dr. Ben
contact affiliation	University of Pennsylvania, Biochemistry & Biophysics, Philadelphia, PA, 19104, USA
contact email	blackbe@pennmedicine.upenn.edu
lab head
Emily Smith
contact affiliation	University of Pennsylvania
contact email	espillet@pennmedicine.upenn.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/09/PXD043794

PRIDE project URI

• PRIDE
  1. PXD043794
     1. Label: PRIDE project
     2. Name: A PARP2 active site α-helix melts to permit DNA damage-induced enzymatic activation