Molecular coevolution of coagulation factor VIII and von Willebrand factor

• Type of Material: Article
• Authors: Philip M. Zakas, Queen’s University; Christopher W. Coyle, Emory University; Anja Brehm, Octapharma Biopharmaceuticals GmbH; Marion Bayer, Octapharma Biopharmaceuticals GmbH; Babarbara Solecka-Witulska, Octapharma Biopharmaceuticals GmbH; Caelen E. Radford, Georgia Institute of Technology; Christine Brown, Queen’s University; Kate Nesbitt, Queen’s University; Courtney Dwyer, Queen’s University; Christoph Kannicht, Octapharma Biopharmaceuticals GmbH; H Trent Spencer, Emory University; Eric A. Gaucher, Georgia Institute of Technology; Christopher Doering, Emory University; David Lillicrap, Queen’s University
• Language: English
• Date: 2021-02-09
• Publisher: AMER SOC HEMATOLOGY
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by The American Society of Hematology
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2020002971
• Title of Journal or Parent Work: BLOOD ADVANCES
• Volume: 5
• Issue: 3
• Start Page: 812
• End Page: 822
• Grant/Funding Information: This work was partially supported by CIHR Foundation (grant FDN154285) (D.L.); National Institutes of Health, National Heart, Lung, and Blood Institute (grant HL137128) (C.B.D.); National Institutes of Health, National Institute of Arthritis, Musculoskeletal and Skin Diseases Research (grant R01AR069137) (E.A.G.); Department of Defense (grant MURI W911NF-16-1-0372) (E.A.G.); and Human Frontier Science Program (grant RGP0041) (E.A.G.).
• Keywords: EVOLUTION; IDENTIFICATION; Life Sciences & Biomedicine; SEQUENCE; Hematology; MUTATIONS; BIOSYNTHESIS; DISEASE; HIGH-LEVEL EXPRESSION; Science & Technology; GENE; SECRETION; DOMAINS
• Research Categories: Biology, Cell; Health Sciences, Oncology

Abstract

Ancestral sequence reconstruction provides a unique platform for investigating the molecular evolution of single gene products and recently has shown success in engineering advanced biological therapeutics. To date, the coevolution of proteins within complexes and protein-protein interactions is mostly investigated in silico via proteomics and/or within single-celled systems. Herein, ancestral sequence reconstruction is used to investigate the molecular evolution of 2 proteins linked not only by stabilizing association in circulation but also by their independent roles within the primary and secondary hemostatic systems of mammals. Using sequence analysis and biochemical characterization of recombinant ancestral von Willebrand factor (VWF) and coagulation factor VIII (FVIII), we investigated the evolution of the essential macromolecular FVIII/VWF complex. Our data support the hypothesis that these coagulation proteins coevolved throughout mammalian diversification, maintaining strong binding affinities while modulating independent and distinct hemostatic activities in diverse lineages.