Calmodulin as Ca2+-Dependent Interactor of FTO Dioxygenase

Abstract

FTO is an N6-methyladenosine demethylase removing methyl groups from nucleic acids. Several studies indicate the creation of FTO complexes with other proteins. Here, we looked for regulatory proteins recognizing parts of the FTO dioxygenase region. In the Calmodulin (CaM) Target Database, we found the FTO C-domain potentially binding CaM, and we proved this finding experimentally. The interaction was Ca2+-dependent but independent on FTO phosphorylation. We found that FTO–CaM interaction essentially influences calcium-binding loops in CaM, indicating the presence of two peptide populations—exchanging as CaM alone and differently, suggesting that only one part of CaM interacts with FTO, and the other one reminds free. The modeling of FTO–CaM interaction showed its stable structure when the half of the CaM molecule saturated with Ca2+ interacts with the FTO C-domain, whereas the other part is disconnected. The presented data indicate calmodulin as a new FTO interactor and support engagement of the FTO protein in calcium signaling pathways.

Mobility capillary electrophoresis–native mass spectrometry reveals the dynamic conformational equilibrium of calmodulin and its complexes

“…The structural flexibility of CaM is believed to account for its ability to recognize various targets, and the concentration of Ca 2+ is also critical during this process. 75–78 The binding event of CaM with a peptide ligand, Mel, was then explored. The MCE and native MS results of CaM–Mel mixtures (1 : 1) at different Ca 2+ concentrations are plotted in Fig.…”

Gut microbiota modulates differential lipid metabolism outcomes associated with FTO gene polymorphisms in response to personalized nutrition intervention

“…In a study of 380 adult Iranian women, the lower levels of HDL were observed in the risk genotypes compared to the non-risk genotype of FTO ( 23 ). The mechanism of FTO polymorphism affecting lipid metabolism has not been fully understood, but it has been reported that FTO could interact with calmodulin-dependent protein kinase II (CaMKII), thereby prolonging CREB phosphorylation and affecting the expression levels of Brain-derived neurotrophic factor (BDNF) and NPY1R neuropeptide Y receptor Y1 (NPY1R), which were related to lipid metabolic process ( 24 ). Besides, FTO catalyzes the demethylation of m6A to alter the processing, maturation, and translation of the mRNAs of lipid-related genes ( 25 ).…”