Publications
Publications, Books, Book Chapters and Reviews by Prof. Marcus Maurer, MD
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A mutation in the kringle domain of human factor XII that causes autoinflammation, disturbs zymogen quiescence and accelerates activation
Filename | 371. Hofman et al, Mutation in the kringle factor XII, JBC 2020.pdf |
Filesize | 2.33 MB |
Version | o.371 |
Date added | June 5, 2020 |
Downloaded | 3 times |
Category | Original Work |
Tags | autoinflammation |
Authors | Hofman, Z. L. M., Clark, C. C., Sanrattana, W., Nosairi, A., Parr, N., Zivkovic, M., Krause, K., Mahnke, N. A., Scheffel, J., Hack, C. E., Maurer, M., de Maat, S., and Maas, C. |
Citation | Hofman, Z. L. M., Clark, C. C., Sanrattana, W., Nosairi, A., Parr, N., Zivkovic, M., Krause, K., Mahnke, N. A., Scheffel, J., Hack, C. E., Maurer, M., de Maat, S., and Maas, C.: A mutation in the kringle domain of human factor XII that causes autoinflammation, disturbs zymogen quiescence and accelerates activation. J. Biol. Chem. 2020: 295; 363-374. |
Corresponding authors | Maas, C. |
DocNum | o.371 |
DocType | |
Edition; Page | 295; 363-374 |
IF | 5.16 |
Publisher | J. Biol. Chem. |
ReleaseDate | 2020 |
Coagulation factor XII (FXII) drives production of the inflammatory peptide bradykinin. Pathological mutations in the F12 gene, which encodes FXII, provoke acute tissue swelling in hereditary angioedema (HAE). Interestingly, a recently identified F12 mutation, causing a W268R substitution, is not associated with HAE. Instead, FXII-W268R carriers experience coldinducible urticarial rash, arthralgia, fever, and fatigue. Here, we aimed to investigate the molecular characteristics of the FXIIW268R variant. We expressed wild type FXII (FXII-WT), FXIIW268R, and FXII-T309R (which causes HAE), as well as other FXII variants in HEK293 freestyle cells. Using chromogenic substrate assays, immunoblotting, and ELISA, we analyzed expression media, cell lysates, and purified proteins for FXII activation. Recombinant FXII-W268R forms increased amounts of intracellular cleavage products that are also present in expression medium and display enzymatic activity. The active site– incapacitated variant FXII-W268R/S544A reveals that intracellular fragmentation is largely dependent on autoactivation. Purified FXII-W268R is highly sensitive to activation by plasma kallikrein and plasmin, compared with FXII-WT or FXIIT309R. Furthermore, binding studies indicated that the FXIIW268R variant leads to the exposure of a plasminogen-binding site that is cryptic in FXII-WT. In plasma, recombinant FXIIW268R spontaneously triggers high-molecular-weight kininogen cleavage. Our findings suggest that the W268R substitution influences FXII protein conformation and exposure of the activation loop, which is concealed in FXII-WT. This results in intracellular autoactivation and constitutive low-grade secretion of activated FXII. These findings help to explain the chronically increased contact activation in carriers of the FXIIW268R variant.
(Last update: 12.2023)
Number of original publications in peer-reviewed journals: | 580 |
Number of reviews in peer-reviewed journals: | 210 |
Number of publications (original work and reviews) in peer-reviewed journals: | 790 |
Cumulative IF for original publications in peer-reviewed journals: | 4196.39 |
Cumulative IF for reviews in peer-reviewed journals: | 1409.32 |
Cumulative IF of publications (original work & reviews) in peer-reviewed journals: | 5605.71 |
Total number of citations: 36,836, h-index: 99 (Web of Science December 2023) | 36836 |
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