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Polyphosphate and tyrosine phosphorylation in the N-terminal domain of the human mitochondrial Lon protease disrupts its functions

N. Kunová, G. Ondrovičová, JA. Bauer, V. Krajčovičová, M. Pinkas, B. Stojkovičová, H. Havalová, V. Lukáčová, L. Kohútová, J. Košťan, L. Martináková, P. Baráth, J. Nováček, S. Zoll, S. Kereϊche, E. Kutejová, V. Pevala

. 2024 ; 14 (1) : 9923. [pub] 20240430

Language English Country England, Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc24014230

Grant support
894 Grant No. 1825144Y Grantová Agentura České Republiky
894 Grant No. 1825144Y Grantová Agentura České Republiky
894 Grant No. 1825144Y Grantová Agentura České Republiky
StruBioMol, ITMS: 305011X666 Interreg
StruBioMol, ITMS: 305011X666 Interreg
StruBioMol, ITMS: 305011X666 Interreg
StruBioMol, ITMS: 305011X666 Interreg
StruBioMol, ITMS: 305011X666 Interreg
UP CIISB (No. CZ.02.1.01/0.0/0.0/18_046/0015974) European Regional Development Fund, European Union
UP CIISB (No. CZ.02.1.01/0.0/0.0/18_046/0015974) European Regional Development Fund, European Union
BIOMEDIRES - II. stage, ITMS: 313011W428 European Regional Development Fund
APVV-15-0375, APVV-19-0298 Agentúra na Podporu Výskumu a Vývoja
APVV-15-0375, APVV-19-0298 Agentúra na Podporu Výskumu a Vývoja
2/0069/23 Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
2/0069/23 Vedecká Grantová Agentúra MŠVVaŠ SR a SAV

Phosphorylation plays a crucial role in the regulation of many fundamental cellular processes. Phosphorylation levels are increased in many cancer cells where they may promote changes in mitochondrial homeostasis. Proteomic studies on various types of cancer identified 17 phosphorylation sites within the human ATP-dependent protease Lon, which degrades misfolded, unassembled and oxidatively damaged proteins in mitochondria. Most of these sites were found in Lon's N-terminal (NTD) and ATPase domains, though little is known about the effects on their function. By combining the biochemical and cryo-electron microscopy studies, we show the effect of Tyr186 and Tyr394 phosphorylations in Lon's NTD, which greatly reduce all Lon activities without affecting its ability to bind substrates or perturbing its tertiary structure. A substantial reduction in Lon's activities is also observed in the presence of polyphosphate, whose amount significantly increases in cancer cells. Our study thus provides an insight into the possible fine-tuning of Lon activities in human diseases, which highlights Lon's importance in maintaining proteostasis in mitochondria.

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$a Polyphosphate and tyrosine phosphorylation in the N-terminal domain of the human mitochondrial Lon protease disrupts its functions / $c N. Kunová, G. Ondrovičová, JA. Bauer, V. Krajčovičová, M. Pinkas, B. Stojkovičová, H. Havalová, V. Lukáčová, L. Kohútová, J. Košťan, L. Martináková, P. Baráth, J. Nováček, S. Zoll, S. Kereϊche, E. Kutejová, V. Pevala
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$a Phosphorylation plays a crucial role in the regulation of many fundamental cellular processes. Phosphorylation levels are increased in many cancer cells where they may promote changes in mitochondrial homeostasis. Proteomic studies on various types of cancer identified 17 phosphorylation sites within the human ATP-dependent protease Lon, which degrades misfolded, unassembled and oxidatively damaged proteins in mitochondria. Most of these sites were found in Lon's N-terminal (NTD) and ATPase domains, though little is known about the effects on their function. By combining the biochemical and cryo-electron microscopy studies, we show the effect of Tyr186 and Tyr394 phosphorylations in Lon's NTD, which greatly reduce all Lon activities without affecting its ability to bind substrates or perturbing its tertiary structure. A substantial reduction in Lon's activities is also observed in the presence of polyphosphate, whose amount significantly increases in cancer cells. Our study thus provides an insight into the possible fine-tuning of Lon activities in human diseases, which highlights Lon's importance in maintaining proteostasis in mitochondria.
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