Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation

Ivanov, Ivan and Matafonov, Anton and Sun, Mao-fu and Cheng, Qiufang and Dickeson, S. Kent and Verhamme, Ingrid M. and Emsley, Jonas and Gailani, David (2017) Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation. Blood, 129 . pp. 1527-1537. ISSN 1528-0020

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Abstract

When blood is exposed to variety of artificial surfaces and biologic substances, the plasma proteins factor XII (FXII) and prekallikrein undergo reciprocal proteolytic conversion to the proteases αFXIIa and α-kallikrein by a process called contact activation. These enzymes contribute to host-defense responses including coagulation, inflammation, and fibrinolysis. The initiating event in contact activation is debated. To test the hypothesis that single-chain FXII expresses activity that could initiate contact activation, we prepared human FXII variants lacking the Arg353 cleavage site required for conversion to αFXIIa (FXII-R353A), or lacking the 3 known cleavage sites at Arg334, Arg343, and Arg353 (FXII-T, for “triple” mutant), and compared their properties to wild-type αFXIIa. In the absence of a surface, FXII-R353A and FXII-T activate prekallikrein and cleave the tripeptide S-2302, demonstrating proteolytic activity. The activity is several orders of magnitude weaker than that of αFXIIa. Polyphosphate, an inducer of contact activation, enhances PK activation by FXII-T, and facilitates FXII-T activation of FXII and FXI. In plasma, FXII-T and FXII-R353A, but not FXII lacking the active site serine residue (FXII-S544A), shortened the clotting time of FXII-deficient plasma and enhanced thrombin generation in a surface-dependent manner. The effect was not as strong as for wild-type FXII. Our results support a model for induction of contact activation in which activity intrinsic to single-chain FXII initiates αFXIIa and α-kallikrein formation on a surface. αFXIIa, with support from α-kallikrein, subsequently accelerates contact activation and is responsible for the full procoagulant activity of FXII.

Item Type: Article
Additional Information: This research was originally published in Blood. Ivan Ivanov, Anton Matafonov, Mao-fu Sun, Qiufang Cheng, S. Kent Dickeson, Ingrid M. Verhamme, Jonas Emsley and David Gailani. Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation. Blood. 2017;129:1527-1537. © the American Society of Hematology
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number: 10.1182/blood-2016-10-744110
Depositing User: emsley, prof jonas
Date Deposited: 16 Aug 2017 08:47
Last Modified: 24 Nov 2017 12:50
URI: http://eprints.nottingham.ac.uk/id/eprint/44922

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