PXD039489-1

PXD039489 is an original dataset announced via ProteomeXchange.

Title	Thrombin activation of the factor XI dimer is a multi-staged process for each subunit
Description	Factor XI (FXI) is a protein in the intrinsic coagulation pathway that can be activated by two enzymes. In hemostasis, FXI is activated by thrombin, while FXIIa-mediated activation of FXI is thought to be prothrombotic. The interactions of these enzymes with FXI are poorly understood due to their transient nature which is difficult to study. Here, we applied crosslinking mass spectrometry (XLMS) and molecular dynamics simulations to investigate the binding interface between thrombin and FXI as well as the dynamics underlying the activation of FXI. From the experimental data we were able to construct the FXI homodimer as well as locate the binding interface of thrombin on the light chain of FXI. As this placed thrombin distal from both the activation site as well as the apple 1 domain that thrombin is known to interact with, we applied molecular dynamics simulations to investigate the chain of events after binding. From the resulting model, we hypothesize that the activation of FXI is a multi-staged procedure where thrombin first binds to Pro520 on FXI, after which it migrates towards the activation site by first engaging the apple 1 domain and finally Arg378. We validated the results with known mutation sites on FXI and additionally found that Pro520 is conserved in PK and enables binding of thrombin to this enzyme even though it cannot be activated by it. This interaction points a way for future interventions for bleeding and thrombosis.
HostingRepository	PRIDE
AnnounceDate	2024-02-05
AnnouncementXML	Submission_2024-02-05_07:11:32.025.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Richard Scheltema
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	2023-01-16 13:50:40	ID requested
⏵ 1	2024-02-05 07:11:32	announced

Bar Barroeta A, Albanese P, Kadav, á T, Jankevics A, Marquart JA, Meijers JCM, Scheltema RA, Thrombin activation of the factor XI dimer is a multistaged process for each subunit. J Thromb Haemost, 22(5):1336-1346(2024) [pubmed]

10.1016/j.jtha.2023.12.038;

submitter keyword: molecular dynamics,Factor XI, crosslinking mass spectrometry, PhoX, thrombin

Richard Scheltema
contact affiliation	Utrecht University
contact email	r.a.scheltema@uu.nl
lab head
Richard Scheltema
contact affiliation	Utrecht University
contact email	r.a.scheltema@uu.nl
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/2024/02/PXD039489

PRIDE project URI

• PRIDE
  1. PXD039489
     1. Label: PRIDE project
     2. Name: Thrombin activation of the factor XI dimer is a multi-staged process for each subunit