“Sirtilins – the new old members of the vitamin K-dependent coagulationfactor family”
Sven O. Dahms, Fatih Demir, Pitter F. Huesgen, Karina Thorn and Hans Brandstetter
Abstract:
Background
Vitamin K (VK)‐dependent proteases are major players in blood coagulation including the initiation as well as the regulation of the cascade. Five different members of this protease family have been described comprising the coagulation factors VII (FVII), IX (FIX), X (FX), protein C (PC) and prothrombin (FII). FVII, FIX, FX and PC share a typical domain architecture with a N‐terminal Gla (γ‐carboxyglutamate)‐domain, two EGF (epidermal growth factor‐like)‐domains and a C‐terminal trypsin‐like serine protease (SP)‐domain.

Objectives
We have identified so far uncharacterized proteins in snake genomes showing the typical Gla‐EGF1‐EGF2‐SP domain architecture but relatively low sequence conservation to known VK‐dependent proteases. Based on 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 factor XIa. The activated form of sirtilin proteolytically cleaved peptide and protein substrates including prothrombin. Mass spectrometry based substrate profiling (PICS) of sirtilin revealed a narrower sequence specificity compared to 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.

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Reviewed by Angela Risch

CONGRATULATIONS!