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Flexibility of the thrombin-activatable fibrinolysis inhibitor pro-domain enables productive binding of protein substrates

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Flexibility of the thrombin-activatable fibrinolysis inhibitor pro-domain enables productive binding of protein substrates. / Valnickova, Zuzana; Sanglas, Laura; Arolas, Joan L; Petersen, Steen V; Schar, Christine; Otzen, Daniel; Aviles, Francesc X; Gomis-Ruth, F Xavier; Enghild, Jan J.

I: Journal of Biological Chemistry, 2010.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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Valnickova, Zuzana ; Sanglas, Laura ; Arolas, Joan L ; Petersen, Steen V ; Schar, Christine ; Otzen, Daniel ; Aviles, Francesc X ; Gomis-Ruth, F Xavier ; Enghild, Jan J. / Flexibility of the thrombin-activatable fibrinolysis inhibitor pro-domain enables productive binding of protein substrates. I: Journal of Biological Chemistry. 2010.

Bibtex

@article{70448b70ee5711dfa891000ea68e967b,
title = "Flexibility of the thrombin-activatable fibrinolysis inhibitor pro-domain enables productive binding of protein substrates",
abstract = "We have previously reported that thrombin-activatable fibrinolysis inhibitor (TAFI) exhibits intrinsic proteolytic activity towards large peptides. The structural basis for this observation was clarified by the crystal structures of human and bovine TAFI. These structures evinced a significant rotation of the pro-domain away from the catalytic moiety when compared to other pro-carboxypeptidases, thus enabling access of large peptide substrates to the active-site cleft. Here we further investigated the flexible nature of the pro-domain and demonstrated that TAFI forms productive complexes with protein carboxypeptidase inhibitors from potato, leech, and tick (PCI, LCI, and TCI, respectively). We determined the crystal structure of the bovine TAFI-TCI complex, revealing that the pro-domain was completely displaced from the position observed in the TAFI structure. It protruded into the bulk solvent and was disordered, whereas TCI occupied the position previously held by the pro-domain. The authentic nature of the presently studied TAFI-inhibitor complexes was supported by the trimming of the C-terminal residues from the three inhibitors upon complex formation. This finding suggests that the inhibitors interact with the active site of TAFI in a substrate-like manner. Taken together, these data show for the first time that TAFI is able to form a bona fide complex with protein carboxypeptidase inhibitors. This underlines the unusually flexible nature of the pro-domain and implies a possible mechanism for regulation of TAFI intrinsic proteolytic activity in vivo.",
author = "Zuzana Valnickova and Laura Sanglas and Arolas, {Joan L} and Petersen, {Steen V} and Christine Schar and Daniel Otzen and Aviles, {Francesc X} and Gomis-Ruth, {F Xavier} and Enghild, {Jan J}",
year = "2010",
doi = "10.1074/jbc.M110.150342",
language = "English",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",

}

RIS

TY - JOUR

T1 - Flexibility of the thrombin-activatable fibrinolysis inhibitor pro-domain enables productive binding of protein substrates

AU - Valnickova, Zuzana

AU - Sanglas, Laura

AU - Arolas, Joan L

AU - Petersen, Steen V

AU - Schar, Christine

AU - Otzen, Daniel

AU - Aviles, Francesc X

AU - Gomis-Ruth, F Xavier

AU - Enghild, Jan J

PY - 2010

Y1 - 2010

N2 - We have previously reported that thrombin-activatable fibrinolysis inhibitor (TAFI) exhibits intrinsic proteolytic activity towards large peptides. The structural basis for this observation was clarified by the crystal structures of human and bovine TAFI. These structures evinced a significant rotation of the pro-domain away from the catalytic moiety when compared to other pro-carboxypeptidases, thus enabling access of large peptide substrates to the active-site cleft. Here we further investigated the flexible nature of the pro-domain and demonstrated that TAFI forms productive complexes with protein carboxypeptidase inhibitors from potato, leech, and tick (PCI, LCI, and TCI, respectively). We determined the crystal structure of the bovine TAFI-TCI complex, revealing that the pro-domain was completely displaced from the position observed in the TAFI structure. It protruded into the bulk solvent and was disordered, whereas TCI occupied the position previously held by the pro-domain. The authentic nature of the presently studied TAFI-inhibitor complexes was supported by the trimming of the C-terminal residues from the three inhibitors upon complex formation. This finding suggests that the inhibitors interact with the active site of TAFI in a substrate-like manner. Taken together, these data show for the first time that TAFI is able to form a bona fide complex with protein carboxypeptidase inhibitors. This underlines the unusually flexible nature of the pro-domain and implies a possible mechanism for regulation of TAFI intrinsic proteolytic activity in vivo.

AB - We have previously reported that thrombin-activatable fibrinolysis inhibitor (TAFI) exhibits intrinsic proteolytic activity towards large peptides. The structural basis for this observation was clarified by the crystal structures of human and bovine TAFI. These structures evinced a significant rotation of the pro-domain away from the catalytic moiety when compared to other pro-carboxypeptidases, thus enabling access of large peptide substrates to the active-site cleft. Here we further investigated the flexible nature of the pro-domain and demonstrated that TAFI forms productive complexes with protein carboxypeptidase inhibitors from potato, leech, and tick (PCI, LCI, and TCI, respectively). We determined the crystal structure of the bovine TAFI-TCI complex, revealing that the pro-domain was completely displaced from the position observed in the TAFI structure. It protruded into the bulk solvent and was disordered, whereas TCI occupied the position previously held by the pro-domain. The authentic nature of the presently studied TAFI-inhibitor complexes was supported by the trimming of the C-terminal residues from the three inhibitors upon complex formation. This finding suggests that the inhibitors interact with the active site of TAFI in a substrate-like manner. Taken together, these data show for the first time that TAFI is able to form a bona fide complex with protein carboxypeptidase inhibitors. This underlines the unusually flexible nature of the pro-domain and implies a possible mechanism for regulation of TAFI intrinsic proteolytic activity in vivo.

U2 - 10.1074/jbc.M110.150342

DO - 10.1074/jbc.M110.150342

M3 - Journal article

C2 - 20880845

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

ER -