Complete abolishment of coagulant activity in monomeric disulfide-deficient tissue factor.

摘要

The initiator of coagulation, tissue factor (TF), resides on the cell surface in an inactive (cryptic) state that binds factor VIIa with reduced affinity and cannot activate factor X, or in an active (decrypted), conformation. Protein disulfide isomerase-dependent regulation of the TF allosteric Cys~186-Cys~209 disulfide has been proposed as a key event in TF decryption, but this remains controversial. Although elimination of the TF disulfide by Cys~209-to-Ala conversion reduces affinity for VIIa and abolishes procoagulant activity, Kothari et al have questioned the validity of the disulfide switching model of TF decryption. They showed that mutation of either Cys-residue to Ser led to 10-fold lower cellular TF expression compared with wild-type TF, but coagulant activity normalized per TF molecule at supraphysiologic VIIa concentrations was indistinguishable between mutants and wild-type TF.