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

• Type of Material: Article
• Authors: Chan Li, University of Nottingham; Kayleigh M. Voos, Emory University; Monika Pathak, University of Nottingham; Gareth Hall, University of Nottingham; Keith R. McCrae, Cleveland Clinic; Ingrid Dreveny, University of Nottingham; Renhao Li, Emory University; Jonas Emsley, University of Nottingham
• Language: English
• Date: 2019-05-01
• Publisher: Wiley
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1111/jth.14418
• Title of Journal or Parent Work: Journal of Thrombosis and Haemostasis
• Volume: 17
• Issue: 5
• Start Page: 759
• End Page: 770
• Keywords: Prekalikkrein; Binding sites; Peripheral Vascular Disease; Activation; Molecular weight kininogen; factor XII; plasma kallikrein; Identification; System; Science & Technology; Cardiovascular System & Cardiology; Thrombin; factor IX; factor XI; Coagulation; kininogens; Life Sciences & Biomedicine; Factor IX; Mechanisms; Hematology
• Research Categories: Biology, Molecular; Biology, Cell; Health Sciences, Oncology

Abstract

Background: 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. 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 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.