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

DOI: 10.1182/blood-2016-10-744110 DOI Help

Authors: Ivan Ivanov (Vanderbilt University Medical Center) , Anton Matafonov (Vanderbilt University Medical Center; Tomsk Polytechnic University) , Mao-Fu Sun (Vanderbilt University Medical Center) , Qiufang Cheng (Vanderbilt University Medical Center) , S. Kent Dickeson (Vanderbilt University Medical Center) , Ingrid M. Verhamme (Vanderbilt University Medical Center) , Jonas Emsley (University of Nottingham) , David Gailani (Vanderbilt University Medical Center)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Blood , VOL 129 , PAGES 1527 - 1537

State: Published (Approved)
Published: March 2017
Diamond Proposal Number(s): 14692

Open Access Open Access

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.

Journal Keywords: cytokinesis; endopeptidases; factor xii; kininogenase; peptide hydrolases; plasma; proteolysis; serine; thrombin; blood coagulation

Diamond Keywords: Thrombosis

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 17/09/2018 14:56


Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)