Tissue factor（TF）, the cell surface receptor and requisite cofactor for the inactive serine protease factor VⅡa（VⅡa）, binds VⅡa and its zymogen factor VⅡ with picomolar affinity on the cell surface. The TF：V...Tissue factor（TF）, the cell surface receptor and requisite cofactor for the inactive serine protease factor VⅡa（VⅡa）, binds VⅡa and its zymogen factor VⅡ with picomolar affinity on the cell surface. The TF：VⅡa complex proteolytically converts downstream zymogen factors X and IX to their active protease states in the cascade responsible for thrombogenesis and hemostasis. The TF pathway also produces cellular signaling through protease activated receptors. Here we present a crystal structure of the completely intact surface domain of TF in complex with VⅡa that reveals a significant conformational difference as compared to free TF. A long loop of residue 78~91 of the tissue factor（named Ω loop here） was found to have well-ordered conformation, whereas this loop in free TF has an expanded conformation and is largely disordered. This loop adopts a tight conformation consisting of five β turns in the TF：VⅡa complex. The Ω loop is located at the interface of the proteins of the complex, has a few interactions with VⅡa, and is possible to accommodate the sequence variations of TF in different mammalian species.展开更多
基金financially supported by grants from National Natural Science Foundation of China(31370737,31400637,31570745,31670739)Ministry of Science and Technology(2017YFE0103200)
文摘Tissue factor（TF）, the cell surface receptor and requisite cofactor for the inactive serine protease factor VⅡa（VⅡa）, binds VⅡa and its zymogen factor VⅡ with picomolar affinity on the cell surface. The TF：VⅡa complex proteolytically converts downstream zymogen factors X and IX to their active protease states in the cascade responsible for thrombogenesis and hemostasis. The TF pathway also produces cellular signaling through protease activated receptors. Here we present a crystal structure of the completely intact surface domain of TF in complex with VⅡa that reveals a significant conformational difference as compared to free TF. A long loop of residue 78~91 of the tissue factor（named Ω loop here） was found to have well-ordered conformation, whereas this loop in free TF has an expanded conformation and is largely disordered. This loop adopts a tight conformation consisting of five β turns in the TF：VⅡa complex. The Ω loop is located at the interface of the proteins of the complex, has a few interactions with VⅡa, and is possible to accommodate the sequence variations of TF in different mammalian species.
