Reformable intramolecular cross-linking of the N-terminal domain of heparin cofactor II - Effects on enzyme inhibition

Brinkmeyer S, Eckert R, Ragg H (2004)
EUROPEAN JOURNAL OF BIOCHEMISTRY 271(21): 4275-4283.

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Autor*in
Brinkmeyer, Stephan; Eckert, Ralf; Ragg, HermannUniBi
Abstract / Bemerkung
The crystal structure of a heparin cofactor II (HCII)-thrombin Michaelis complex has revealed extensive contacts encompassing the N-terminal domain of HCII and exosite I of the proteinase. In contrast, the location of the N-terminal extension in the uncomplexed inhibitor was unclear. Using a disulfide cross-linking strategy, we demonstrate that at least three different sites (positions 52, 54 and 68) within the N terminus may be tethered in a reformable manner to position 195 in the loop region between helix D and strand s2A of the HCII molecule, suggesting that the N-terminal domain may interact with the inhibitor scaffold in a permissive manner. Cross-linking of the N terminus to the HCII body does not strongly affect the inhibition of alpha-chymotrypsin, indicating that the reactive site loop sequences of the engineered inhibitor variants, required for interaction with one of the HCII target enzymes, are normally accessible. In contrast, intramolecular tethering of the N-terminal extension results in a drastic decrease of alpha-thrombin inhibitory activity, both in the presence and in the absence of glycosaminoglycans. Treatment with dithiothreitol and iodoacetamide restores activity towards alpha-thrombin, suggesting that release of the N terminus of HCII is an important component of the multistep interaction between the inhibitor and alpha-thrombin.
Stichworte
dermatan sulfate; serpin(s); heparin; alpha-thrombin; heparin cofactor II
Erscheinungsjahr
2004
Zeitschriftentitel
EUROPEAN JOURNAL OF BIOCHEMISTRY
Band
271
Ausgabe
21
Seite(n)
4275-4283
ISSN
0014-2956
Page URI
https://pub.uni-bielefeld.de/record/1606208

Zitieren

Brinkmeyer S, Eckert R, Ragg H. Reformable intramolecular cross-linking of the N-terminal domain of heparin cofactor II - Effects on enzyme inhibition. EUROPEAN JOURNAL OF BIOCHEMISTRY. 2004;271(21):4275-4283.
Brinkmeyer, S., Eckert, R., & Ragg, H. (2004). Reformable intramolecular cross-linking of the N-terminal domain of heparin cofactor II - Effects on enzyme inhibition. EUROPEAN JOURNAL OF BIOCHEMISTRY, 271(21), 4275-4283. https://doi.org/10.1111/j.1432-1033.2004.04367.x
Brinkmeyer, Stephan, Eckert, Ralf, and Ragg, Hermann. 2004. “Reformable intramolecular cross-linking of the N-terminal domain of heparin cofactor II - Effects on enzyme inhibition”. EUROPEAN JOURNAL OF BIOCHEMISTRY 271 (21): 4275-4283.
Brinkmeyer, S., Eckert, R., and Ragg, H. (2004). Reformable intramolecular cross-linking of the N-terminal domain of heparin cofactor II - Effects on enzyme inhibition. EUROPEAN JOURNAL OF BIOCHEMISTRY 271, 4275-4283.
Brinkmeyer, S., Eckert, R., & Ragg, H., 2004. Reformable intramolecular cross-linking of the N-terminal domain of heparin cofactor II - Effects on enzyme inhibition. EUROPEAN JOURNAL OF BIOCHEMISTRY, 271(21), p 4275-4283.
S. Brinkmeyer, R. Eckert, and H. Ragg, “Reformable intramolecular cross-linking of the N-terminal domain of heparin cofactor II - Effects on enzyme inhibition”, EUROPEAN JOURNAL OF BIOCHEMISTRY, vol. 271, 2004, pp. 4275-4283.
Brinkmeyer, S., Eckert, R., Ragg, H.: Reformable intramolecular cross-linking of the N-terminal domain of heparin cofactor II - Effects on enzyme inhibition. EUROPEAN JOURNAL OF BIOCHEMISTRY. 271, 4275-4283 (2004).
Brinkmeyer, Stephan, Eckert, Ralf, and Ragg, Hermann. “Reformable intramolecular cross-linking of the N-terminal domain of heparin cofactor II - Effects on enzyme inhibition”. EUROPEAN JOURNAL OF BIOCHEMISTRY 271.21 (2004): 4275-4283.

9 Zitationen in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

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