Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia
Essential thrombocythemia (ET) is a blood cancer. ET is characterized by an overproduction of platelets that can lead to thrombosis formation. Platelet overproduction occurs in megakaryocytes through a signaling pathway that could involve JAK2, MPL, or CALR proteins. CALR mutations are associated wi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/3/509 |
| _version_ | 1797613233543053312 |
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| author | Ragousandirane Radjasandirane Alexandre G. de Brevern |
| author_facet | Ragousandirane Radjasandirane Alexandre G. de Brevern |
| author_sort | Ragousandirane Radjasandirane |
| collection | DOAJ |
| description | Essential thrombocythemia (ET) is a blood cancer. ET is characterized by an overproduction of platelets that can lead to thrombosis formation. Platelet overproduction occurs in megakaryocytes through a signaling pathway that could involve JAK2, MPL, or CALR proteins. CALR mutations are associated with 25–30% of ET patients; CALR variants must be dimerized to induce ET. We classified these variants into five classes named A to E; classes A and B are the most frequent classes in patients with ET. The dynamic properties of these five classes using structural models of CALR’s C-domain were analyzed using molecular dynamics simulations. Classes A, B, and C are associated with frameshifts in the C-domain. Their dimers can be stable only if a disulfide bond is formed; otherwise, the two monomers repulse each other. Classes D and E cannot be stable as dimers due to the absence of disulfide bonds. Class E and wild-type CALR have similar dynamic properties. These results suggest that the disulfide bond newly formed in classes A, B, and C may be essential for the pathogenicity of these variants. They also underline that class E cannot be directly related to ET but corresponds to human polymorphisms. |
| first_indexed | 2024-03-11T06:52:59Z |
| format | Article |
| id | doaj.art-dc84e5043b65496d9b89b68ea7d38315 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T06:52:59Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-dc84e5043b65496d9b89b68ea7d383152023-11-17T09:52:18ZengMDPI AGBiomolecules2218-273X2023-03-0113350910.3390/biom13030509Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential ThrombocythemiaRagousandirane Radjasandirane0Alexandre G. de Brevern1Université Paris Cité and Université de la Réunion and Université des Antilles, INSERM, BIGR, DSIMB Bioinformatics Team, F-75014 Paris, FranceUniversité Paris Cité and Université de la Réunion and Université des Antilles, INSERM, BIGR, DSIMB Bioinformatics Team, F-75014 Paris, FranceEssential thrombocythemia (ET) is a blood cancer. ET is characterized by an overproduction of platelets that can lead to thrombosis formation. Platelet overproduction occurs in megakaryocytes through a signaling pathway that could involve JAK2, MPL, or CALR proteins. CALR mutations are associated with 25–30% of ET patients; CALR variants must be dimerized to induce ET. We classified these variants into five classes named A to E; classes A and B are the most frequent classes in patients with ET. The dynamic properties of these five classes using structural models of CALR’s C-domain were analyzed using molecular dynamics simulations. Classes A, B, and C are associated with frameshifts in the C-domain. Their dimers can be stable only if a disulfide bond is formed; otherwise, the two monomers repulse each other. Classes D and E cannot be stable as dimers due to the absence of disulfide bonds. Class E and wild-type CALR have similar dynamic properties. These results suggest that the disulfide bond newly formed in classes A, B, and C may be essential for the pathogenicity of these variants. They also underline that class E cannot be directly related to ET but corresponds to human polymorphisms.https://www.mdpi.com/2218-273X/13/3/509CALR mutationsmolecular dynamicsessential thrombocythemiachronic myeloproliferative neoplasmsblood cancerdisulfide bonds |
| spellingShingle | Ragousandirane Radjasandirane Alexandre G. de Brevern Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia Biomolecules CALR mutations molecular dynamics essential thrombocythemia chronic myeloproliferative neoplasms blood cancer disulfide bonds |
| title | Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia |
| title_full | Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia |
| title_fullStr | Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia |
| title_full_unstemmed | Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia |
| title_short | Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia |
| title_sort | structural and dynamic differences between calreticulin mutants associated with essential thrombocythemia |
| topic | CALR mutations molecular dynamics essential thrombocythemia chronic myeloproliferative neoplasms blood cancer disulfide bonds |
| url | https://www.mdpi.com/2218-273X/13/3/509 |
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