Autocitrullination of PAD4 does not alter its enzymatic activity: In vitro and in silico studies

Liu, Xiaosong; Wichapong, Kanin; Lamers, Sebastiaan; Reutelingsperger, Chris; Nicolaes, Gerry A. F.

doi:10.1016/j.biocel.2021.105938

Cited by 9 publications

(12 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PAD4 has been shown to be capable of citrullinating itself on several positions, which was shown to affect PAD4 protein–protein interactions 46 . Regarding the effect of auto‐citrullination on PAD4 activity, we showed in a recent publication that PAD4 auto‐citrullination has no effect on its activity 47 …”

Section: Activation and Regulation Of Pad4 Activitymentioning

confidence: 88%

See 1 more Smart Citation

PAD4 takes charge during neutrophil activation: Impact of PAD4 mediated NET formation on immune‐mediated disease

Liu

Arfman

Wichapong

et al. 2021

Journal of Thrombosis and Haemostasis

Self Cite

101

View full text Add to dashboard Cite

Background: Peptidyl arginine deiminase 4 (PAD4) is an enzyme that converts arginine into citrulline. PAD4 is expressed in neutrophils that, when activated, can drive the formation of neutrophil extracellular traps (NETs). Uncontrolled activation of PAD4 and subsequent citrullination of proteins is increasingly recognized as a driver of (auto)immune diseases. Currently, our understanding of PAD4 structure–function relationships and activity control in vivo is incomplete. Aims: To provide the current state‐of‐the‐art on PAD4 structure‐activity relationships and involvement of PAD4 in autoimmune disorders as well as in thrombo‐inflammatory disease. Materials & Methods: Literature review and molecular modelling Results: In this review, we used molecular modelling to generate a three‐dimensional structure of the complete PAD4 molecule. Using our model, we discuss the catalytic conversion of the arginine substrate to citrulline. Besides mechanistic insight into PAD4 function, we give an overview of biological functions of PAD4 and mechanisms that influence its activation. In addition, we discuss the crucial role of PAD4‐mediated citrullination of histones during the formation of NETs. Subsequently, we focus on the role of PAD4‐mediated NET formation and its role in pathogenesis of rheumatoid arthritis, sepsis and (immune‐)thrombosis. Finally, we summarize current efforts to design different classes of PAD4 inhibitors that are being developed for improved treatment of autoimmune disorders as well as thrombo‐inflammatory disease. Discussion: Advances in PAD4 structure‐function are still necessary to gain a complete insight in mechanisms that control PAD4 activity in vivo. The involvement of PAD4 in several diseases signifies the need for a PAD4 inhibitor. Although progress has been made to produce an isotype specific and potent PAD4 inhibitor, currently no PAD4 inhibitor is ready for clinical use. Conclusion: More research into PAD4 structure and function and into the regulation of its activity is required for the development of PAD4 specific inhibitors that may prove vital to combat and prevent autoimmune disorders and (thrombo)inflammatory disease.

show abstract

Section: Activation and Regulation Of Pad4 Activitymentioning

confidence: 88%

“… 46 Regarding the effect of auto‐citrullination on PAD4 activity, we showed in a recent publication that PAD4 auto‐citrullination has no effect on its activity. 47 …”

Section: Activation and Regulation Of Pad4 Activitymentioning

confidence: 99%

PAD4 takes charge during neutrophil activation: Impact of PAD4 mediated NET formation on immune‐mediated disease

Liu

Arfman

Wichapong

et al. 2021

Journal of Thrombosis and Haemostasis

Self Cite

101

View full text Add to dashboard Cite

show abstract

“…The GPIbα-VWF A1 domain complex and the GPIbα-VWF A1-botrocetin complex (PDB code: 1U0N) were subjected to molecular dynamics (MD) simulations in order to identify key interacting residues at the interface according to a previously established method [37,52]. Herein, AMBER14SB force fields were assigned for proteins and a TIP3P water model was used and added to a 10 Å radius of the molecular surface of the complex.…”

Section: Molecular Dynamics and Binding Free-energy Calculationsmentioning

confidence: 99%

Structure-Based Cyclic Glycoprotein Ibα-Derived Peptides Interfering with von Willebrand Factor-Binding, Affecting Platelet Aggregation under Shear

Hrdinová

Fernández

Ercig

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

The plasmatic von Willebrand factor (VWF) circulates in a compact form unable to bind platelets. Upon shear stress, the VWF A1 domain is exposed, allowing VWF-binding to platelet glycoprotein Ib-V-IX (GPIbα chain). For a better understanding of the role of this interaction in cardiovascular disease, molecules are needed to specifically interfere with the opened VWF A1 domain interaction with GPIbα. Therefore, we in silico designed and chemically synthetized stable cyclic peptides interfering with the platelet-binding of the VWF A1 domain per se or complexed with botrocetin. Selected peptides (26–34 amino acids) with the lowest-binding free energy were: the monocyclic mono- vOn Willebrand factoR-GPIbα InTerference (ORbIT) peptide and bicyclic bi-ORbIT peptide. Interference of the peptides in the binding of VWF to GPIb-V-IX interaction was retained by flow cytometry in comparison with the blocking of anti-VWF A1 domain antibody CLB-RAg35. In collagen and VWF-dependent whole-blood thrombus formation at a high shear rate, CLB-RAg35 suppressed stable platelet adhesion as well as the formation of multilayered thrombi. Both peptides phenotypically mimicked these changes, although they were less potent than CLB-RAg35. The second-round generation of an improved peptide, namely opt-mono-ORbIT (28 amino acids), showed an increased inhibitory activity under flow. Accordingly, our structure-based design of peptides resulted in physiologically effective peptide-based inhibitors, even for convoluted complexes such as GPIbα-VWF A1.

show abstract

“…To build the cyclic peptides Arg-and Lyseptifibatide, the homoarginine residue (hArg) of eptifibatide was mutated in silico to Arg or Lys, respectively. The αIIbβ3-eptifibatide/Argeptifibatide/Lys-eptifibatide complexes were subjected to MD simulations by using similar protocols and parameters as in recent work [15,16], AMBER14SB force field was assigned for the protein (αIIbβ3) and the cyclic peptides (eptifibatide/Arg-eptifibatide/Lys-eptifibatide), and explicit TIP3P water model was used. Prior to running MD simulations, energy minimization was first employed to relax the systems by applying 5000 steps of steepest descent followed by 5000 steps of conjugate gradient algorithm.…”

Section: Molecular Dynamics (Md) Simulationsmentioning

confidence: 99%

Unraveling the role of the homoarginine residue in antiplatelet drug eptifibatide in binding to the αIIbβ3 integrin receptor

Kerkhof¹,

Nagy²,

Wichapong

et al. 2022

Thrombosis Research

Self Cite

View full text Add to dashboard Cite

Autocitrullination of PAD4 does not alter its enzymatic activity: In vitro and in silico studies

Cited by 9 publications

References 31 publications

PAD4 takes charge during neutrophil activation: Impact of PAD4 mediated NET formation on immune‐mediated disease

PAD4 takes charge during neutrophil activation: Impact of PAD4 mediated NET formation on immune‐mediated disease

Structure-Based Cyclic Glycoprotein Ibα-Derived Peptides Interfering with von Willebrand Factor-Binding, Affecting Platelet Aggregation under Shear

Unraveling the role of the homoarginine residue in antiplatelet drug eptifibatide in binding to the αIIbβ3 integrin receptor

Contact Info

Product

Resources

About