A Structural Model for Bax∆2-Mediated Activation of Caspase 8-Dependent Apoptosis
Bax∆2 is a pro-apoptotic anti-tumor protein in the Bax family. While most of the Bax family causes cell death by targeting mitochondria, Bax∆2 forms cytosolic aggregates and activates caspase 8-dependent cell death. We previously showed that the Bax∆2 helix α9 is critical for caspase 8 recruitment....
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-07-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/15/5476 |
| _version_ | 1797560684173590528 |
|---|---|
| author | Bing Xie Qi Yao Jialing Xiang David D.L. Minh |
| author_facet | Bing Xie Qi Yao Jialing Xiang David D.L. Minh |
| author_sort | Bing Xie |
| collection | DOAJ |
| description | Bax∆2 is a pro-apoptotic anti-tumor protein in the Bax family. While most of the Bax family causes cell death by targeting mitochondria, Bax∆2 forms cytosolic aggregates and activates caspase 8-dependent cell death. We previously showed that the Bax∆2 helix α9 is critical for caspase 8 recruitment. However, the interaction between these two proteins at the structural level is unknown. In this in silico study, we performed molecular dynamics (MD) simulations and protein–protein docking on Bax∆2 variants. The results suggest that the Bax∆2 variants have different stable states. Mutating the Baxα mitochondria-targeting signal [L26P/L27P] appears to introduce a kink into helix α1. Protein–protein docking suggests that helices α9 of both wild-type Bax∆2 and Bax∆2 caspase 8 binding-deficient mutant [L164P] can fit in the same caspase 8 binding site, but the mutant is unable to fit as well as wild-type Bax∆2. Together, these data point to a structural basis for explaining Bax∆2 function in caspase 8-dependent cell death. |
| first_indexed | 2024-03-10T18:04:09Z |
| format | Article |
| id | doaj.art-5f5e567a4dc64c8180f81fc6b9e1d003 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T18:04:09Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5f5e567a4dc64c8180f81fc6b9e1d0032023-11-20T08:37:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-07-012115547610.3390/ijms21155476A Structural Model for Bax∆2-Mediated Activation of Caspase 8-Dependent ApoptosisBing Xie0Qi Yao1Jialing Xiang2David D.L. Minh3Department of Chemistry, Illinois Institute of Technology, Chicago, IL 60616, USADepartment of Biology, Illinois Institute of Technology, Chicago, IL 60616, USADepartment of Biology, Illinois Institute of Technology, Chicago, IL 60616, USADepartment of Chemistry, Illinois Institute of Technology, Chicago, IL 60616, USABax∆2 is a pro-apoptotic anti-tumor protein in the Bax family. While most of the Bax family causes cell death by targeting mitochondria, Bax∆2 forms cytosolic aggregates and activates caspase 8-dependent cell death. We previously showed that the Bax∆2 helix α9 is critical for caspase 8 recruitment. However, the interaction between these two proteins at the structural level is unknown. In this in silico study, we performed molecular dynamics (MD) simulations and protein–protein docking on Bax∆2 variants. The results suggest that the Bax∆2 variants have different stable states. Mutating the Baxα mitochondria-targeting signal [L26P/L27P] appears to introduce a kink into helix α1. Protein–protein docking suggests that helices α9 of both wild-type Bax∆2 and Bax∆2 caspase 8 binding-deficient mutant [L164P] can fit in the same caspase 8 binding site, but the mutant is unable to fit as well as wild-type Bax∆2. Together, these data point to a structural basis for explaining Bax∆2 function in caspase 8-dependent cell death.https://www.mdpi.com/1422-0067/21/15/5476apoptosisBaxcaspasecell deathcomputational biologyhomology modeling |
| spellingShingle | Bing Xie Qi Yao Jialing Xiang David D.L. Minh A Structural Model for Bax∆2-Mediated Activation of Caspase 8-Dependent Apoptosis International Journal of Molecular Sciences apoptosis Bax caspase cell death computational biology homology modeling |
| title | A Structural Model for Bax∆2-Mediated Activation of Caspase 8-Dependent Apoptosis |
| title_full | A Structural Model for Bax∆2-Mediated Activation of Caspase 8-Dependent Apoptosis |
| title_fullStr | A Structural Model for Bax∆2-Mediated Activation of Caspase 8-Dependent Apoptosis |
| title_full_unstemmed | A Structural Model for Bax∆2-Mediated Activation of Caspase 8-Dependent Apoptosis |
| title_short | A Structural Model for Bax∆2-Mediated Activation of Caspase 8-Dependent Apoptosis |
| title_sort | structural model for bax∆2 mediated activation of caspase 8 dependent apoptosis |
| topic | apoptosis Bax caspase cell death computational biology homology modeling |
| url | https://www.mdpi.com/1422-0067/21/15/5476 |
| work_keys_str_mv | AT bingxie astructuralmodelforbax2mediatedactivationofcaspase8dependentapoptosis AT qiyao astructuralmodelforbax2mediatedactivationofcaspase8dependentapoptosis AT jialingxiang astructuralmodelforbax2mediatedactivationofcaspase8dependentapoptosis AT daviddlminh astructuralmodelforbax2mediatedactivationofcaspase8dependentapoptosis AT bingxie structuralmodelforbax2mediatedactivationofcaspase8dependentapoptosis AT qiyao structuralmodelforbax2mediatedactivationofcaspase8dependentapoptosis AT jialingxiang structuralmodelforbax2mediatedactivationofcaspase8dependentapoptosis AT daviddlminh structuralmodelforbax2mediatedactivationofcaspase8dependentapoptosis |