Insertion Depth Modulates Protein Kinase C-δ-C1b Domain Interactions with Membrane Cholesterol as Revealed by MD Simulations
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 bry...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/5/4598 |
| _version_ | 1797615164742172672 |
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| author | Patrick T. Judge Sarah A. Overall Alexander B. Barnes |
| author_facet | Patrick T. Judge Sarah A. Overall Alexander B. Barnes |
| author_sort | Patrick T. Judge |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T07:22:38Z |
| format | Article |
| id | doaj.art-70f025b301e74930853f1734da0920a0 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T07:22:38Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-70f025b301e74930853f1734da0920a02023-11-17T07:50:43ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01245459810.3390/ijms24054598Insertion Depth Modulates Protein Kinase C-δ-C1b Domain Interactions with Membrane Cholesterol as Revealed by MD SimulationsPatrick T. Judge0Sarah A. Overall1Alexander B. Barnes2Department of Biochemistry, Biophysics & Structural Biology, Washington University in St. Louis, St. Louis, MO 63130, USALaboratory of Physical Chemistry, ETH Zürich, 8093 Zurich, SwitzerlandLaboratory of Physical Chemistry, ETH Zürich, 8093 Zurich, SwitzerlandProtein 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.https://www.mdpi.com/1422-0067/24/5/4598protein kinase Ccholesterolbryostatinphorbol estersmolecular dynamicsmembrane bilayer |
| spellingShingle | Patrick T. Judge Sarah A. Overall Alexander B. Barnes Insertion Depth Modulates Protein Kinase C-δ-C1b Domain Interactions with Membrane Cholesterol as Revealed by MD Simulations International Journal of Molecular Sciences protein kinase C cholesterol bryostatin phorbol esters molecular dynamics membrane bilayer |
| title | Insertion Depth Modulates Protein Kinase C-δ-C1b Domain Interactions with Membrane Cholesterol as Revealed by MD Simulations |
| title_full | Insertion Depth Modulates Protein Kinase C-δ-C1b Domain Interactions with Membrane Cholesterol as Revealed by MD Simulations |
| title_fullStr | Insertion Depth Modulates Protein Kinase C-δ-C1b Domain Interactions with Membrane Cholesterol as Revealed by MD Simulations |
| title_full_unstemmed | Insertion Depth Modulates Protein Kinase C-δ-C1b Domain Interactions with Membrane Cholesterol as Revealed by MD Simulations |
| title_short | Insertion Depth Modulates Protein Kinase C-δ-C1b Domain Interactions with Membrane Cholesterol as Revealed by MD Simulations |
| title_sort | insertion depth modulates protein kinase c δ c1b domain interactions with membrane cholesterol as revealed by md simulations |
| topic | protein kinase C cholesterol bryostatin phorbol esters molecular dynamics membrane bilayer |
| url | https://www.mdpi.com/1422-0067/24/5/4598 |
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