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Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI
Author(s): ,
Chan Li
Affiliations:
Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK
,
Kayleigh M. Voos
Affiliations:
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, USA
,
Monika Pathak
Affiliations:
Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK
,
Gareth Hall
Affiliations:
Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK
,
Keith R. McCrae
Affiliations:
Departments of Hematology and Oncology and Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, USA
,
Ingrid Dreveny
Affiliations:
Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK
,
Renhao Li
Affiliations:
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, USA
Jonas Emsley
Affiliations:
Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK
Correspondence: Jonas Emsley, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK|Tel.: +44 115 846 7092|E‐mail: jonas.emsley@nottingham.ac.uk
ISTH Academy. Emsley J.
May 1, 2019; 273612
Prof. Jonas Emsley
Prof. Jonas Emsley
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Journal Abstract
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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.
Keyword(s)
factor IX, factor XI, factor XII, kininogens, plasma kallikrein
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