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A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain

DOI: 10.1182/blood-2015-10-676122 DOI Help

Authors: S. S. Wong (University of Nottingham) , S. Ostergaard (Novo Nordisk, Malov, Denmark) , G. Hall (University of Nottingham) , C. Li (University of Nottingham) , P. M. Williams (University of Nottingham) , H. Stennicke (University of Nottingham) , J. Emsley (University of Nottingham)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Blood , VOL 127 , PAGES 2915–2923

State: Published (Approved)
Published: March 2016
Diamond Proposal Number(s): 14692 , 10369

Abstract: Factor XI (FXI) is the zymogen of factor XIa (FXIa) which cleaves factor IX in the intrinsic pathway of coagulation. FXI is known to exist as a dimer and form interactions with multiple proteins via its four apple domains in the "saucer section" of the enzyme however to date, no complex crystal structure has been described. To investigate protein interactions of FXI a large random peptide library consisting of 106-107 peptides was screened for FXI binding and this identified a series of FXI binding motifs containing the signature Asp-Phe-Pro (DFP) tripeptide. Motifs containing this core tripeptide were found in diverse proteins including the known ligand high molecular weight kininogen (HK) as well as extracellular matrix proteins laminin and collagen V. To define the binding site on FXI we determined the crystal structure of FXI in complex with the HK derived peptide NPISDFPDT. This revealed the location of the DFP peptide bound to the FXI apple 2 domain and central to the interaction the DFP phenylalanine side chain inserts into a major hydrophobic pocket in the apple 2 domain and the isoleucine occupies a flanking minor pocket. Two further structures of FXI in complex with the laminin derived peptide EFPDFP and a DFP peptide from the random screen demonstrated binding in the same pocket although in a slightly different conformation, thus revealing some flexibility in the molecular interactions of the FXI apple 2 domain.

Subject Areas: Biology and Bio-materials

Instruments: I04-Macromolecular Crystallography

Other Facilities: ESRF

Added On: 06/04/2016 15:42

Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)