Coupled Electrostatic and Hydrophobic Destabilisation of the Gelsolin-Actin Complex Enables Facile Detection of Ovarian Cancer Biomarker Lysophosphatidic Acid
Lysophosphatidic acid (LPA) is a promising biomarker candidate to screen for ovarian cancer (OC) and potentially stratify and treat patients according to disease stage. LPA is known to target the actin-binding protein gelsolin which is a key regulator of actin filament assembly. Previous studies hav...
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MDPI AG
2023-09-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/9/1426 |
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| author | Katharina Davoudian Shayon Bhattacharya Damien Thompson Michael Thompson |
| author_facet | Katharina Davoudian Shayon Bhattacharya Damien Thompson Michael Thompson |
| author_sort | Katharina Davoudian |
| collection | DOAJ |
| description | Lysophosphatidic acid (LPA) is a promising biomarker candidate to screen for ovarian cancer (OC) and potentially stratify and treat patients according to disease stage. LPA is known to target the actin-binding protein gelsolin which is a key regulator of actin filament assembly. Previous studies have shown that the phosphate headgroup of LPA alone is inadequate to bind to the short chain of amino acids in gelsolin known as the PIP<sub>2</sub>-binding domain. Thus, the molecular-level detail of the mechanism of LPA binding is poorly understood. Here, we model LPA binding to the PIP<sub>2</sub>-binding domain of gelsolin in the gelsolin-actin complex through extensive ten-microsecond atomistic molecular dynamics (MD) simulations. We predict that LPA binding causes a local conformational rearrangement due to LPA interactions with both gelsolin and actin residues. These conformational changes are a result of the amphipathic nature of LPA, where the anionic phosphate, polar glycerol and ester groups, and lipophilic aliphatic tail mediate LPA binding via charged electrostatic, hydrogen bonding, and van der Waals interactions. The negatively-charged LPA headgroup binds to the PIP<sub>2</sub>-binding domain of gelsolin-actin while its hydrophobic tail is inserted into actin, creating a strong LPA-insertion pocket that weakens the gelsolin–actin interface. The computed structure, dynamics, and energetics of the ternary gelsolin–LPA–actin complex confirms that a quantitative OC assay is possible based on LPA-triggered actin release from the gelsolin-actin complex. |
| first_indexed | 2024-03-10T22:59:02Z |
| format | Article |
| id | doaj.art-1bd88a9e64b6484ea3ae8fe4a978d91e |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T22:59:02Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-1bd88a9e64b6484ea3ae8fe4a978d91e2023-11-19T09:46:48ZengMDPI AGBiomolecules2218-273X2023-09-01139142610.3390/biom13091426Coupled Electrostatic and Hydrophobic Destabilisation of the Gelsolin-Actin Complex Enables Facile Detection of Ovarian Cancer Biomarker Lysophosphatidic AcidKatharina Davoudian0Shayon Bhattacharya1Damien Thompson2Michael Thompson3Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, CanadaSSPC—The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, IrelandSSPC—The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, IrelandDepartment of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, CanadaLysophosphatidic acid (LPA) is a promising biomarker candidate to screen for ovarian cancer (OC) and potentially stratify and treat patients according to disease stage. LPA is known to target the actin-binding protein gelsolin which is a key regulator of actin filament assembly. Previous studies have shown that the phosphate headgroup of LPA alone is inadequate to bind to the short chain of amino acids in gelsolin known as the PIP<sub>2</sub>-binding domain. Thus, the molecular-level detail of the mechanism of LPA binding is poorly understood. Here, we model LPA binding to the PIP<sub>2</sub>-binding domain of gelsolin in the gelsolin-actin complex through extensive ten-microsecond atomistic molecular dynamics (MD) simulations. We predict that LPA binding causes a local conformational rearrangement due to LPA interactions with both gelsolin and actin residues. These conformational changes are a result of the amphipathic nature of LPA, where the anionic phosphate, polar glycerol and ester groups, and lipophilic aliphatic tail mediate LPA binding via charged electrostatic, hydrogen bonding, and van der Waals interactions. The negatively-charged LPA headgroup binds to the PIP<sub>2</sub>-binding domain of gelsolin-actin while its hydrophobic tail is inserted into actin, creating a strong LPA-insertion pocket that weakens the gelsolin–actin interface. The computed structure, dynamics, and energetics of the ternary gelsolin–LPA–actin complex confirms that a quantitative OC assay is possible based on LPA-triggered actin release from the gelsolin-actin complex.https://www.mdpi.com/2218-273X/13/9/1426ovarian cancerlysophosphatidic acidgelsolinactinlipid-protein interactionpredictive molecular modelling |
| spellingShingle | Katharina Davoudian Shayon Bhattacharya Damien Thompson Michael Thompson Coupled Electrostatic and Hydrophobic Destabilisation of the Gelsolin-Actin Complex Enables Facile Detection of Ovarian Cancer Biomarker Lysophosphatidic Acid Biomolecules ovarian cancer lysophosphatidic acid gelsolin actin lipid-protein interaction predictive molecular modelling |
| title | Coupled Electrostatic and Hydrophobic Destabilisation of the Gelsolin-Actin Complex Enables Facile Detection of Ovarian Cancer Biomarker Lysophosphatidic Acid |
| title_full | Coupled Electrostatic and Hydrophobic Destabilisation of the Gelsolin-Actin Complex Enables Facile Detection of Ovarian Cancer Biomarker Lysophosphatidic Acid |
| title_fullStr | Coupled Electrostatic and Hydrophobic Destabilisation of the Gelsolin-Actin Complex Enables Facile Detection of Ovarian Cancer Biomarker Lysophosphatidic Acid |
| title_full_unstemmed | Coupled Electrostatic and Hydrophobic Destabilisation of the Gelsolin-Actin Complex Enables Facile Detection of Ovarian Cancer Biomarker Lysophosphatidic Acid |
| title_short | Coupled Electrostatic and Hydrophobic Destabilisation of the Gelsolin-Actin Complex Enables Facile Detection of Ovarian Cancer Biomarker Lysophosphatidic Acid |
| title_sort | coupled electrostatic and hydrophobic destabilisation of the gelsolin actin complex enables facile detection of ovarian cancer biomarker lysophosphatidic acid |
| topic | ovarian cancer lysophosphatidic acid gelsolin actin lipid-protein interaction predictive molecular modelling |
| url | https://www.mdpi.com/2218-273X/13/9/1426 |
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