Molecular coevolution of coagulation factor VIII and von Willebrand factor

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.

Autoinhibitory module underlies species difference in shear activation of von Willebrand factor

“…Additional evidence for a weaker mouse AIM can be found in a recent investigation into ancestral reconstruction of VWF 49 . Compared to human VWF, full‐length variant An88 derived from a lineage of rodents shows increased GPIbα‐dependent activity, whereas An101 from a lineage of primates shows decreased activity, which the authors attributed to sequence differences within the AIM, not A1 49 …”

“…Replacement of key binding interfaces within human VWF (residues 1326–1333 and 1370–1385 in the A1 domain) to mouse‐specific sequences was unable to correct bleeding in mice, suggesting that this mutant human VWF may not be properly activated in the mouse, possibly due to the strong protection provided by the human AIM 15 . Additional evidence for a weaker mouse AIM can be found in a recent investigation into ancestral reconstruction of VWF 49 . Compared to human VWF, full‐length variant An88 derived from a lineage of rodents shows increased GPIbα‐dependent activity, whereas An101 from a lineage of primates shows decreased activity, which the authors attributed to sequence differences within the AIM, not A1 49 …”

“…49 Compared to human VWF, full-length variant An88 derived from a lineage of rodents shows increased GPIbα-dependent activity, whereas An101 from a lineage of primates shows decreased activity, which the authors attributed to sequence differences within the not A1. 49 The binding of VWF to platelets must occur under high shear conditions, and under force, the human LBD-A1 interaction is strengthened, that is, a catch-bond is formed. 50 This catch-bond behavior is essential to slow platelets down during elongational flows that occur during vessel injury due to vasoconstriction.…”

“…14 However, this mutation is not necessary for mouse VWF to bind human GPIbα and maintain hemostasis in hTg mice and another similar strain. 49 Compared to human VWF, full-length variant An88 derived from a lineage of rodents shows increased GPIbα-dependent activity, whereas An101 from a lineage of primates shows decreased activity, which the authors attributed to sequence differences within the not A1. 49 The binding of VWF to platelets must occur under high shear conditions, and under force, the human LBD-A1 interaction is strengthened, that is, a catch-bond is formed.…”

CRISPR-Cas9-mediated reactivation of the uricase pseudogene in human cells prevents acute hyperuricemia

“…We have also extended the biomedical utility of ancient proteins to treat/prevent diseases. 32 , 33 , 34 , 35 We further anticipate that future studies will provide more insights into the advantages and/or disadvantages of uric acid’s role as a critical antioxidant and its connection to the loss of vitamin C synthesis in the Haplorhini clade of mammals (tarsiers, monkeys, and apes). 5 , 6 , 8 , 36 , 37 …”