Cancer-Related Mutations in the Sam Domains of EphA2 Receptor and Ship2 Lipid Phosphatase: A Computational Study
The lipid phosphatase Ship2 interacts with the EphA2 receptor by forming a heterotypic Sam (sterile alpha motif)–Sam complex. Ship2 works as a negative regulator of receptor endocytosis and consequent degradation, and anti-oncogenic effects in cancer cells should be induced by hindering its associat...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-02-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/29/5/1024 |
| _version_ | 1797264189010477056 |
|---|---|
| author | Marian Vincenzi Flavia Anna Mercurio Ida Autiero Marilisa Leone |
| author_facet | Marian Vincenzi Flavia Anna Mercurio Ida Autiero Marilisa Leone |
| author_sort | Marian Vincenzi |
| collection | DOAJ |
| description | The lipid phosphatase Ship2 interacts with the EphA2 receptor by forming a heterotypic Sam (sterile alpha motif)–Sam complex. Ship2 works as a negative regulator of receptor endocytosis and consequent degradation, and anti-oncogenic effects in cancer cells should be induced by hindering its association with EphA2. Herein, a computational approach is presented to investigate the relationship between Ship2-Sam/EphA2-Sam interaction and cancer onset and further progression. A search was first conducted through the COSMIC (Catalogue of Somatic Mutations in Cancer) database to identify cancer-related missense mutations positioned inside or close to the EphA2–Sam and Ship2–Sam reciprocal binding interfaces. Next, potential differences in the chemical–physical properties of mutant and wild-type Sam domains were evaluated by bioinformatics tools based on analyses of primary sequences. Three-dimensional (3D) structural models of mutated EphA2–Sam and Ship2–Sam domains were built as well and deeply analysed with diverse computational instruments, including molecular dynamics, to classify potentially stabilizing and destabilizing mutations. In the end, the influence of mutations on the EphA2–Sam/Ship2–Sam interaction was studied through docking techniques. This in silico approach contributes to understanding, at the molecular level, the mutation/cancer relationship by predicting if amino acid substitutions could modulate EphA2 receptor endocytosis. |
| first_indexed | 2024-04-25T00:24:56Z |
| format | Article |
| id | doaj.art-ec9ca8ac40024d119eca2f3a6a207315 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-25T00:24:56Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-ec9ca8ac40024d119eca2f3a6a2073152024-03-12T16:50:48ZengMDPI AGMolecules1420-30492024-02-01295102410.3390/molecules29051024Cancer-Related Mutations in the Sam Domains of EphA2 Receptor and Ship2 Lipid Phosphatase: A Computational StudyMarian Vincenzi0Flavia Anna Mercurio1Ida Autiero2Marilisa Leone3Institute of Biostructures and Bioimaging, Via Pietro Castellino 111, 80131 Naples, ItalyInstitute of Biostructures and Bioimaging, Via Pietro Castellino 111, 80131 Naples, ItalyInstitute of Biostructures and Bioimaging, Via Pietro Castellino 111, 80131 Naples, ItalyInstitute of Biostructures and Bioimaging, Via Pietro Castellino 111, 80131 Naples, ItalyThe lipid phosphatase Ship2 interacts with the EphA2 receptor by forming a heterotypic Sam (sterile alpha motif)–Sam complex. Ship2 works as a negative regulator of receptor endocytosis and consequent degradation, and anti-oncogenic effects in cancer cells should be induced by hindering its association with EphA2. Herein, a computational approach is presented to investigate the relationship between Ship2-Sam/EphA2-Sam interaction and cancer onset and further progression. A search was first conducted through the COSMIC (Catalogue of Somatic Mutations in Cancer) database to identify cancer-related missense mutations positioned inside or close to the EphA2–Sam and Ship2–Sam reciprocal binding interfaces. Next, potential differences in the chemical–physical properties of mutant and wild-type Sam domains were evaluated by bioinformatics tools based on analyses of primary sequences. Three-dimensional (3D) structural models of mutated EphA2–Sam and Ship2–Sam domains were built as well and deeply analysed with diverse computational instruments, including molecular dynamics, to classify potentially stabilizing and destabilizing mutations. In the end, the influence of mutations on the EphA2–Sam/Ship2–Sam interaction was studied through docking techniques. This in silico approach contributes to understanding, at the molecular level, the mutation/cancer relationship by predicting if amino acid substitutions could modulate EphA2 receptor endocytosis.https://www.mdpi.com/1420-3049/29/5/1024Sam domainEphA2Ship2Mid Loop (ML)End Helix (EH)AlphaFold2 |
| spellingShingle | Marian Vincenzi Flavia Anna Mercurio Ida Autiero Marilisa Leone Cancer-Related Mutations in the Sam Domains of EphA2 Receptor and Ship2 Lipid Phosphatase: A Computational Study Molecules Sam domain EphA2 Ship2 Mid Loop (ML) End Helix (EH) AlphaFold2 |
| title | Cancer-Related Mutations in the Sam Domains of EphA2 Receptor and Ship2 Lipid Phosphatase: A Computational Study |
| title_full | Cancer-Related Mutations in the Sam Domains of EphA2 Receptor and Ship2 Lipid Phosphatase: A Computational Study |
| title_fullStr | Cancer-Related Mutations in the Sam Domains of EphA2 Receptor and Ship2 Lipid Phosphatase: A Computational Study |
| title_full_unstemmed | Cancer-Related Mutations in the Sam Domains of EphA2 Receptor and Ship2 Lipid Phosphatase: A Computational Study |
| title_short | Cancer-Related Mutations in the Sam Domains of EphA2 Receptor and Ship2 Lipid Phosphatase: A Computational Study |
| title_sort | cancer related mutations in the sam domains of epha2 receptor and ship2 lipid phosphatase a computational study |
| topic | Sam domain EphA2 Ship2 Mid Loop (ML) End Helix (EH) AlphaFold2 |
| url | https://www.mdpi.com/1420-3049/29/5/1024 |
| work_keys_str_mv | AT marianvincenzi cancerrelatedmutationsinthesamdomainsofepha2receptorandship2lipidphosphataseacomputationalstudy AT flaviaannamercurio cancerrelatedmutationsinthesamdomainsofepha2receptorandship2lipidphosphataseacomputationalstudy AT idaautiero cancerrelatedmutationsinthesamdomainsofepha2receptorandship2lipidphosphataseacomputationalstudy AT marilisaleone cancerrelatedmutationsinthesamdomainsofepha2receptorandship2lipidphosphataseacomputationalstudy |