The structure-function relationship of activated protein C. Lessons from natural and engineered mutations

Area of Science:

• Biochemistry
• Molecular Biology
• Hematology

Background:

• Activated protein C (APC) is central to the natural anticoagulant pathway.
• APC regulates coagulation by proteolyzing factors V and VIII, attenuating thrombin formation.
• APC possesses direct cytoprotective effects, including maintaining endothelial barrier function and exhibiting anti-inflammatory and anti-apoptotic activities.

Purpose of the Study:

• To review the current understanding of the intricate structure-function relationships of APC.
• To elucidate the molecular mechanisms underlying APC's anticoagulant and cytoprotective functions.
• To highlight the roles of various receptors in APC signaling.

Main Methods:

• Review of existing literature on APC structure and function.
• Analysis of mutagenesis studies to map APC functions onto its 3D structure.
• Discussion of identified receptors involved in APC signaling, including protease-activated receptor 1 (PAR1), EPCR, S1PR1, CD11b/CD18, and TIE2.

Main Results:

• APC's anticoagulant activity is dependent on cofactors like protein S, thrombomodulin, EPCR, and a phospholipid surface.
• Cytoprotective effects of APC are mediated through receptors such as PAR1 and EPCR, with other receptors like S1PR1, CD11b/CD18, and TIE2 also playing significant roles.
• Structure-function studies have provided substantial insights into how APC's structure dictates its diverse functions.

Conclusions:

• APC is a multifunctional protein crucial for maintaining both humoral and tissue homeostasis.
• Understanding APC's structure-function relationships is vital for dissecting its complex biological roles.
• Further research into APC signaling pathways may reveal therapeutic potential.