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Sirtilins – the new old members of the vitamin K‐dependent coagulation factor family
Author(s): ,
Sven O. Dahms
Affiliations:
Department of Biosciences, University of Salzburg, Salzburg, Austria
Correspondence: Sven O. Dahms, Department of Biosciences, University of Salzburg, Billrothstr. 11, A‐5020 Salzburg, Austria|Tel.: +43 662 8044 7277|E‐mail: sven.dahms@sbg.ac.at
,
Fatih Demir
Affiliations:
ZEA‐3 Analytics, Central Institute for Engineering, Electronics and Analytics, Forschungszentrum Jülich, Jülich, Germany
,
Pitter F. Huesgen
Affiliations:
ZEA‐3 Analytics, Central Institute for Engineering, Electronics and Analytics, Forschungszentrum Jülich, Jülich, Germany
,
Karina Thorn
Affiliations:
Haemophilia Research, Novo Nordisk A/S, Måløv, Denmark
Hans Brandstetter
Affiliations:
Department of Biosciences, University of Salzburg, Salzburg, Austria
ISTH Academy. O. Dahms S.
Mar 1, 2019; 273392
Sven O. Dahms
Sven  O. Dahms
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Journal Abstract
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Background
Vitamin K (VK)‐dependent proteases are major players in blood coagulation, including both the initiation and the regulation of the cascade. Five different members of this protease family have been described, comprising the following coagulation factors: factor VII, FIX, FX, protein C (PC), and prothrombin (FII). FVII, FIX, FX and PC share a typical domain architecture, with an N‐terminal γ‐carboxyglutamate (Gla) domain, two epidermal growth factor‐like (EGF) domains, and a C‐terminal trypsin‐like serine protease (SP) domain.
Objectives
We have identified uncharacterized proteins in snake genomes showing the typical Gla–EGF1–EGF2–SP domain architecture but relatively low sequence conservation compared to known VK‐dependent proteases. On the basis of sequence analysis, we hypothesized that these proteins are functional members of the VK‐dependent protease family.
Methods/results
Using phylogenetic analyses, we confirmed the so‐called ‘sirtilins’ as an additional VK‐dependent protease class. These proteases were found in several vertebrates, including jawless fish, cartilaginous fish, bony fish, reptiles, birds, and marsupials, but not in other mammals. The recombinant zymogen form of Thamnophis sirtalis sirtilin was produced by in vitro renaturation, and was activated with human activated FXI. The activated form of sirtilin proteolytically cleaved peptide and protein substrates, including prothrombin. Mass spectrometry‐based substrate profiling of sirtilin revealed a narrower sequence specificity than those of FIX and FX.
Conclusions
The ubiquitous occurrence of sirtilins in many vertebrate classes might indicate an important functional role. Understanding the detailed functions of sirtilins might contribute to a deeper understanding of the evolution and function of the vertebrate coagulation system.
Keyword(s)
blood coagulation factors, hemostasis, mass spectrometry, phylogeny, sequence analysis, trypsin‐like serine protease
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