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Calreticulin mutations affect its chaperone function and perturb the glycoproteome
Patrick M Schürch1, Liliana Malinovska2, Mohammad Hleihil3
1Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.
Cell Reports
|November 23, 2022
Summary
Calreticulin (CALR) mutations in myeloproliferative neoplasms (MPNs) cause glycoprotein structural changes. Homozygous mutations lead to protein misfolding and maturation defects, impacting patient health.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Calreticulin (CALR) is an endoplasmic reticulum (ER) chaperone crucial for glycoprotein folding.
- Mutations in CALR are associated with myeloproliferative neoplasms (MPNs).
- CALR mutants often lack ER retention signals, affecting their function.
Purpose of the Study:
- To investigate the structural and quantitative impact of CALR mutations on proteins, particularly glycoproteins, in MPNs.
- To elucidate the molecular mechanisms underlying CALR mutation-associated pathologies.
- To determine the effect of homozygous versus heterozygous CALR mutations.
Main Methods:
- Limited proteolysis coupled with mass spectrometry (LiP-MS) was employed.
- Analysis was performed on primary patient samples and CALR-mutated cell lines.
- The glycoprotein client myeloperoxidase (MPO) was specifically examined.
Main Results:
- Homozygous CALR mutations significantly alter glycoprotein structure and expression in granulocytes and cell lines.
- Both homozygous CALR mutations and CALR loss-of-function impair glycoprotein integrity.
- Molecular evidence of protein misfolding was observed in homozygous CALR mutation contexts.
Conclusions:
- CALR mutations, especially homozygous ones, disrupt glycoprotein maturation and integrity.
- Loss-of-function mechanisms contribute to the observed defects in MPNs.
- Protein misfolding is a key consequence of homozygous CALR mutations in MPNs.
Keywords:
CP: CancerCP: Molecular biologycalreticulinchaperoneglycoproteinlimited proteolysis-coupled mass spectrometrymyeloperoxidasemyeloproliferative neoplasmprotein foldingproteomeMore Related Videos
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