MPN-274: Mpl is Activated by Dimers of MPN-Linked Calreticulin Mutants Stabilized by Disulfide Bonds and Ionic Interactions

Venkatesan, Arunkumar; Geng, Jie; Kandarpa, Malathi; Wijeyesakere, Sanjeeva J.; Bhide, Ashwini; Talpaz, Moshe; Pogozheva, Irina D.; Raghavan, Malini

doi:10.1016/s2152-2650(20)31001-6

Cited by 1 publication

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“…The dimers were created with MODELLER (i) using previous modeled classes and (ii) adding specific disulfide constraints between cysteines. These systems correspond to what is expected in CALRms associated with ET [ 52 , 53 ]. The simulations were carried out in a similar way as with CALRm classes A, B, and C with an appropriate number of Cl - ions.…”

Section: Resultssupporting

confidence: 80%

“…Venkatesan and co-workers effectively highlighted this with type I, our class A. We reproduced these results by mutating the cysteines, reaching the same conclusion [ 52 , 53 , 83 ]. The analysis of the dynamics is also in good agreement with analyses performed using predictive approaches for disorders by Uversky and collaborators [ 37 , 89 ].…”

Section: Discussionsupporting

confidence: 74%

“…It has been shown that the homomultimerization of mutant calreticulin is an obligatory prerequisite for MPL binding and activation. Recently, Raghavan’s group investigated the relevance of disulfide-bond-mediated interactions in CALRm multimerization in primary patient platelets and human cell lines expressing recombinant mutant CALRms [ 52 , 53 ]. They showed that new cysteine residues in the C-terminal ends of CALRm mutants contributed to CALRm (type 1) and MPL interactions by forming disulfide bridges, both in primary patient platelets and also in human cell lines expressing recombinant CALRm mutants.…”

Section: Introductionmentioning

confidence: 99%

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Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia

Radjasandirane

Brevern

2023

Biomolecules

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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.

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Section: Resultssupporting

confidence: 80%