Engineering a protein Z-dependent protease inhibitor (ZPI) mutant as a novel antagonist of ZPI anticoagulant function for hemophilia treatment.

ABSTRACT:

Background

Protein Z-dependent protease inhibitor (ZPI), is an important anticoagulant protein in plasma that functions in complex with its cofactor, protein Z (PZ) to rapidly inhibit activated factor X (FXa) on a procoagulant membrane surface. Recent studies suggest that the ZPI-PZ anticoagulant complex is a promising target for restoring hemostasis in hemophilia (Girard, et al, J Thromb Haemost, 2019, 17, 149-156).

Objective

Engineering a ZPI mutant as a novel antagonist of ZPI anticoagulant function.

Methods

We engineered two alanine mutations in human ZPI, one in the reactive loop P1 Y387 residue to inactivate the FXa/FXIa inhibitory function, and the second in the K239 binding interface residue to enhance the affinity of the inactive ZPI for PZ. The mutant was ex

SUBMITTER: Huang X 

PROVIDER: S-EPMC8112298 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature