Oncogenic CALR mutant C-terminus mediates dual binding to the thrombopoietin receptor triggering complex dimerization and activation

Nicolas Papadopoulos, Audrey Nédélec, Allison Derenne, Teodor Asvadur Şulea, Christian Pecquet, Ilyas Chachoua, Gaëlle Vertenoeil, Thomas Tilmant, Andrei-Jose Petrescu, Gabriel Mazzucchelli, Bogdan I. Iorga, Didier Vertommen and Stefan N. Constantinescu ()
Additional contact information
Nicolas Papadopoulos: Ludwig Institute for Cancer Research Brussels
Audrey Nédélec: Ludwig Institute for Cancer Research Brussels
Allison Derenne: Spectralys Biotech SRL
Teodor Asvadur Şulea: Institute of Biochemistry of the Romanian Academy
Christian Pecquet: Ludwig Institute for Cancer Research Brussels
Ilyas Chachoua: Ludwig Institute for Cancer Research Brussels
Gaëlle Vertenoeil: Ludwig Institute for Cancer Research Brussels
Thomas Tilmant: Universiy of Liège
Andrei-Jose Petrescu: Institute of Biochemistry of the Romanian Academy
Gabriel Mazzucchelli: Universiy of Liège
Bogdan I. Iorga: Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles
Didier Vertommen: Université catholique de Louvain and de Duve Institute
Stefan N. Constantinescu: Ludwig Institute for Cancer Research Brussels

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Calreticulin (CALR) frameshift mutations represent the second cause of myeloproliferative neoplasms (MPN). In healthy cells, CALR transiently and non-specifically interacts with immature N-glycosylated proteins through its N-terminal domain. Conversely, CALR frameshift mutants turn into rogue cytokines by stably and specifically interacting with the Thrombopoietin Receptor (TpoR), inducing its constitutive activation. Here, we identify the basis of the acquired specificity of CALR mutants for TpoR and define the mechanisms by which complex formation triggers TpoR dimerization and activation. Our work reveals that CALR mutant C-terminus unmasks CALR N-terminal domain, rendering it more accessible to bind immature N-glycans on TpoR. We further find that the basic mutant C-terminus is partially α-helical and define how its α-helical segment concomitantly binds acidic patches of TpoR extracellular domain and induces dimerization of both CALR mutant and TpoR. Finally, we propose a model of the tetrameric TpoR-CALR mutant complex and identify potentially targetable sites.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-37277-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37277-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-37277-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().