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Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

Li, Chan; Voos, Kayleigh M.; Pathak, Monika; Hall, Gareth; McCrae, Keith R.; Dreveny, Ingrid; Li, Renhao; Emsley, Jonas


Chan Li

Kayleigh M. Voos

Research Fellow Inprotein Crystallography

Gareth Hall

Keith R. McCrae

Renhao Li

Professor of Macromolecularcrystallography


Plasma prekallikrein (PK) and factor XI (FXI) are apple domain‐containing serine proteases that when activated to PKa and FXIa cleave substrates kininogen, factor XII, and factor IX, respectively, directing plasma coagulation, bradykinin release, inflammation, and thrombosis pathways.

To investigate the three‐dimensional structure of full‐length PKa and perform a comparison with FXI.

A series of recombinant full‐length PKa and FXI constructs and variants were developed and the crystal structures determined.

Results and conclusions
A 1.3 Å structure of full‐length PKa reveals the protease domain positioned above a disc‐shaped assemblage of four apple domains in an active conformation. A comparison with the homologous FXI structure reveals the intramolecular disulfide and structural differences in the apple 4 domain that prevents dimer formation in PK as opposed to FXI. Two latchlike loops (LL1 and LL2) extend from the PKa protease domain to form interactions with the apple 1 and apple 3 domains, respectively. A major unexpected difference in the PKa structure compared to FXI is the 180° disc rotation of the apple domains relative to the protease domain. This results in a switched configuration of the latch loops such that LL2 interacts and buries portions of the apple 3 domain in the FXI zymogen whereas in PKa LL2 interacts with the apple 1 domain. Hydrogen‐deuterium exchange mass spectrometry on plasma purified human PK and PKa determined that regions of the apple 3 domain have increased surface exposure in PKa compared to the zymogen PK, suggesting conformational change upon activation.

Journal Article Type Article
Publication Date May 1, 2019
Journal Journal of Thrombosis and Haemostasis
Print ISSN 1538-7933
Electronic ISSN 1538-7836
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 17
Issue 5
Pages 759-770
APA6 Citation Li, C., Voos, K. M., Pathak, M., Hall, G., McCrae, K. R., Dreveny, I., …Emsley, J. (2019). Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI. Journal of Thrombosis and Haemostasis, 17(5), 759-770.
Keywords Hematology
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