Insertion Depth Modulates Protein Kinase C-δ-C1b Domain Interactions with Membrane Cholesterol as Revealed by MD Simulations
OPEN ACCESS
Loading...
Author / Producer
Date
2023-03
Publication Type
Journal Article
ETH Bibliography
yes
Citations
Altmetric
OPEN ACCESS
Data
Rights / License
Abstract
Protein kinase C delta (PKC-δ) is an important signaling molecule in human cells that has both proapoptotic as well as antiapoptotic functions. These conflicting activities can be modulated by two classes of ligands, phorbol esters and bryostatins. Phorbol esters are known tumor promoters, while bryostatins have anti-cancer properties. This is despite both ligands binding to the C1b domain of PKC-δ (δC1b) with a similar affinity. The molecular mechanism behind this discrepancy in cellular effects remains unknown. Here, we have used molecular dynamics simulations to investigate the structure and intermolecular interactions of these ligands bound to δC1b with heterogeneous membranes. We observed clear interactions between the δC1b-phorbol complex and membrane cholesterol, primarily through the backbone amide of L250 and through the K256 side-chain amine. In contrast, the δC1b-bryostatin complex did not exhibit interactions with cholesterol. Topological maps of the membrane insertion depth of the δC1b-ligand complexes suggest that insertion depth can modulate δC1b interactions with cholesterol. The lack of cholesterol interactions suggests that bryostatin-bound δC1b may not readily translocate to cholesterol-rich domains within the plasma membrane, which could significantly alter the substrate specificity of PKC-δ compared to δC1b-phorbol complexes.
Permanent link
Publication status
published
External links
Editor
Book title
Journal / series
Volume
24 (5)
Pages / Article No.
4598
Publisher
MDPI
Event
Edition / version
Methods
Software
Geographic location
Date collected
Date created
Subject
protein kinase C; cholesterol; bryostatin; phorbol esters; molecular dynamics; membrane bilayer; lipid rafts
Organisational unit
09681 - Barnes, Alexander / Barnes, Alexander
Notes
Funding
201070 - Dynamic Nuclear Polarization at Room Temperature for High Sensitivity Nuclear Magnetic Resonance (SNF)