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Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation
DOI:
10.1182/blood-2016-10-744110
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

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
Documents:
1527.full.pdf
Discipline Tags:
Structural biology
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)