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

DOI: 10.1111/jth.14418 DOI Help

Authors: Chan Li (University of Nottingham) , Kayleigh M. Voos (Emory University School of Medicine) , Monika Pathak (University of Nottingham) , Gareth Hall (University of Nottingham) , Keith R. Mccrae (Cleveland Clinic) , Ingrid Dreveny (University of Nottingham) , Renhao Li (Emory University School of Medicine) , Jonas Emsley (University of Nottingham)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Thrombosis And Haemostasis

State: Published (Approved)
Published: February 2019
Diamond Proposal Number(s): 19880

Abstract: Background: Plasma prekallikrein (PK) and Factor XI (FXI) are apple domain containing serine proteases which when activated to PKa and FXIa cleave substrates kininogen, Factor XII and Factor IX respectively directing plasma coagulation, bradykinin release, inflammation and thrombosis pathways. Objective: To investigate the three‐dimensional structure of full‐length PKa and perform a comparison with FXI. Methods: 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 disulphide and structural differences in the apple 4 domain that prevents dimer formation in PKa as opposed to FXI. Two latch‐like 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 180º 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 Keywords: Plasma Kallikrein; Factor XI; Factor XII; kininogens; Factor IX

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Other Facilities: ESRF