A molecular dynamics simulation study to understand the effect of cholesterol and tissue factor palmitoylation on tissue factor-factor VIIa-factor Xa ternary complex in different lipid environments.
cholesterol
factor VIIa
factor Xa
molecular dynamics simulation
palmitoylation
protein–lipid interaction
protein–protein interaction
tissue factor
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
09
02
2022
revised:
20
12
2022
accepted:
22
12
2022
medline:
31
3
2023
pubmed:
26
1
2023
entrez:
25
1
2023
Statut:
ppublish
Résumé
Tissue factor (TF), a transmembrane glycoprotein, plays a profound role in the formation of the tissue factor-factor VIIa (TF-FVIIa) complex that initiates factor Xa (FXa) generation followed by thrombin activation and clot formation. Previous reports suggest that TF-FVIIa coagulant activity at the cell surface may be affected by various processes, including changes in cholesterol content and posttranslational modifications of TF. Numerous studies were conducted but yielded inconclusive results about the effect of cholesterol on TF expression. The present study aimed to understand how cholesterol affects structural modulations on the tissue factor-factor VIIa-factor Xa ternary complex (TF-FVIIa-FXa). Additionally, we aimed to illustrate the effect of palmitoylation on the Cys245 residue of TF and understand its structural implications on the TF-FVIIa-FXa. We set up the following 4 systems in different lipid environments: TF-FVIIa-FXa in POPC:POPS (CS), TF-FVIIa-FXa in POPC:POPS:CHOL (CSL), Palmitoylated TF-FVIIa-FXa in POPC:POPS:CHOL (CSLP), and Palmitoylated TF-FVIIa-FXa in POPC:CHOL (CLP), respectively, and subjected them to molecular dynamics simulation. Hydrogen-bond and contact probability analysis were performed between various important domains of TF-FVIIa-FXa and notable novel interactions: Asn93 Analysis of molecular dynamic simulation data suggests that the presence of cholesterol and palmitoylation may contribute to structural rigidity, stability, and compactness of key domains of TF-FVIIa-FXa by augmenting protein-protein and protein-lipid interactions.
Sections du résumé
BACKGROUND
Tissue factor (TF), a transmembrane glycoprotein, plays a profound role in the formation of the tissue factor-factor VIIa (TF-FVIIa) complex that initiates factor Xa (FXa) generation followed by thrombin activation and clot formation. Previous reports suggest that TF-FVIIa coagulant activity at the cell surface may be affected by various processes, including changes in cholesterol content and posttranslational modifications of TF. Numerous studies were conducted but yielded inconclusive results about the effect of cholesterol on TF expression.
OBJECTIVE
The present study aimed to understand how cholesterol affects structural modulations on the tissue factor-factor VIIa-factor Xa ternary complex (TF-FVIIa-FXa). Additionally, we aimed to illustrate the effect of palmitoylation on the Cys245 residue of TF and understand its structural implications on the TF-FVIIa-FXa.
METHODS
We set up the following 4 systems in different lipid environments: TF-FVIIa-FXa in POPC:POPS (CS), TF-FVIIa-FXa in POPC:POPS:CHOL (CSL), Palmitoylated TF-FVIIa-FXa in POPC:POPS:CHOL (CSLP), and Palmitoylated TF-FVIIa-FXa in POPC:CHOL (CLP), respectively, and subjected them to molecular dynamics simulation.
RESULTS
Hydrogen-bond and contact probability analysis were performed between various important domains of TF-FVIIa-FXa and notable novel interactions: Asn93
CONCLUSION
Analysis of molecular dynamic simulation data suggests that the presence of cholesterol and palmitoylation may contribute to structural rigidity, stability, and compactness of key domains of TF-FVIIa-FXa by augmenting protein-protein and protein-lipid interactions.
Identifiants
pubmed: 36696201
pii: S1538-7836(22)19070-7
doi: 10.1016/j.jtha.2022.12.020
pii:
doi:
Substances chimiques
Factor VIIa
EC 3.4.21.21
Factor Xa
EC 3.4.21.6
Lipids
0
Thromboplastin
9035-58-9
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
917-932Informations de copyright
Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest statement There are no competing interests to disclose.