One-Way Allosteric Communication between the Two Disulfide Bonds in Tissue Factor

Area of Science:

• Structural biology
• Biophysics
• Molecular dynamics

Background:

• Tissue factor (TF) is a transmembrane glycoprotein crucial for initiating the extrinsic coagulation cascade and thrombosis.
• TF possesses two disulfide bonds, one in the N-terminal and one in the C-terminal extracellular domain.
• The C-domain disulfide bond (Cys186-Cys209) exhibits a pre-stressed -RHStaple configuration, potentially regulating TF encryption/decryption.

Purpose of the Study:

• To investigate the allosteric communication between TF's N-terminal and C-terminal domains.
• To elucidate the role of disulfide bonds in TF's structural dynamics and allosteric signaling.
• To identify the mechanism and directionality of force propagation within TF.

Main Methods:

• Molecular dynamics (MD) simulations were employed to analyze TF's structural behavior.
• Force distribution analysis was used to detect subtle structural changes upon disulfide bond ablation.
• A shortest-pathway algorithm was utilized to map the force propagation pathway.

Main Results:

• The Cys186-Cys209 disulfide bond maintained its -RHStaple configuration, while the Cys49-Cys57 bond showed significant fluctuation.
• MD simulations revealed distinct properties between the two disulfide bonds, including bond length, angles, and prestress.
• A one-way allosteric communication pathway from the N-terminal to the C-terminal domain was identified.

Conclusions:

• The N-terminal domain exhibits higher stiffness, enabling unidirectional mechanical force propagation to the C-terminal domain.
• This study proposes a novel method for identifying allosteric signal transduction pathways in proteins.
• The findings provide insights into the structural basis of TF function and regulation in coagulation and thrombosis.