Thermodynamics and selection of the plasminogen activator inhibitor-1 latency transition.

ABSTRACT: Plasminogen activator inhibitor-1 (PAI-1), like other serine protease inhibitors, exists in a functionally active metastable conformation. Unlike other serine protease inhibitors, PAI-1 undergoes a relatively rapid rearrangement to a lower energy latent conformation. We employ deep mutational scanning (DMS) to simultaneously probe the effects of nearly all single amino acid substitutions (92%) in PAI-1 on its latency transition as well as its ability to inhibit its canonical protease target, urokinase-type plasminogen activator (uPA). The DMS results are interpreted in the context of variant effect predictors (evolutionary model of variant effect), AlphaMissense, and cross-protein transfer model and protein stability predictors (EvoEF and FoldX), as well as the evolutionary conservation of

SUBMITTER: Haynes LM 

PROVIDER: S-EPMC12702362 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature