A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain
Factor XI (FXI) is the zymogen of FXIa, which cleaves FIX in the intrinsic pathway of coagulation. FXI is known to exist as a dimer and interacts with multiple proteins via its 4 apple domains in the “saucer section” of the enzyme; however, to date, no complex crystal structure has been described. T...
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| Format: | Article |
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American Society of Hematology
2016
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| Online Access: | https://eprints.nottingham.ac.uk/33370/ |
| _version_ | 1848794615478484992 |
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| author | Wong, Szu S. Østergaard, Søren Hall, Gareth Li, Chan Williams, Philip M. Stennicke, Henning Emsley, Jonas |
| author_facet | Wong, Szu S. Østergaard, Søren Hall, Gareth Li, Chan Williams, Philip M. Stennicke, Henning Emsley, Jonas |
| author_sort | Wong, Szu S. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Factor XI (FXI) is the zymogen of FXIa, which cleaves FIX in the intrinsic pathway of coagulation. FXI is known to exist as a dimer and interacts with multiple proteins via its 4 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 to 107 peptides was screened for FXI binding, which 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 the 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. (Blood. 2016;00(00):1-9) |
| first_indexed | 2025-11-14T19:19:01Z |
| format | Article |
| id | nottingham-33370 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:19:01Z |
| publishDate | 2016 |
| publisher | American Society of Hematology |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-333702020-05-04T17:41:08Z https://eprints.nottingham.ac.uk/33370/ A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain Wong, Szu S. Østergaard, Søren Hall, Gareth Li, Chan Williams, Philip M. Stennicke, Henning Emsley, Jonas Factor XI (FXI) is the zymogen of FXIa, which cleaves FIX in the intrinsic pathway of coagulation. FXI is known to exist as a dimer and interacts with multiple proteins via its 4 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 to 107 peptides was screened for FXI binding, which 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 the 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. (Blood. 2016;00(00):1-9) American Society of Hematology 2016-03-22 Article PeerReviewed Wong, Szu S., Østergaard, Søren, Hall, Gareth, Li, Chan, Williams, Philip M., Stennicke, Henning and Emsley, Jonas (2016) A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain. Blood, 127 (23). pp. 2915-2923. ISSN 1528-0020 http://www.bloodjournal.org/content/127/23/2915?sso-checked=true doi:10.1182/blood-2015-10-676122 doi:10.1182/blood-2015-10-676122 |
| spellingShingle | Wong, Szu S. Østergaard, Søren Hall, Gareth Li, Chan Williams, Philip M. Stennicke, Henning Emsley, Jonas A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain |
| title | A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain |
| title_full | A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain |
| title_fullStr | A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain |
| title_full_unstemmed | A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain |
| title_short | A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain |
| title_sort | novel dfp tripeptide motif interacts with the coagulation factor xi apple 2 domain |
| url | https://eprints.nottingham.ac.uk/33370/ https://eprints.nottingham.ac.uk/33370/ https://eprints.nottingham.ac.uk/33370/ |