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Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia.


ABSTRACT: 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.

SUBMITTER: Radjasandirane R 

PROVIDER: S-EPMC10046389 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia.

Radjasandirane Ragousandirane R   de Brevern Alexandre G AG  

Biomolecules 20230310 3


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.  ...[more]

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