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AMPK is an important molecule for regulating biological energy metabolism within cells
.
AMPK can sense intracellular ATP/AMP/ADP levels, phosphorylate downstream specific substrates under low energy supply conditions, reduce ATP consumption, and promote ATP synthesis
.
AMPK consists of
the catalytic subunit AMPKα, the scaffold protein AMPKβ and the regulatory subunit AMPKγ.
The CBS domain of AMPKγ can bind ATP, AMP, ADP, and change the conformation according to its proportions, thereby regulating AMPKα activity
.
.
AMPK can sense intracellular ATP/AMP/ADP levels, phosphorylate downstream specific substrates under low energy supply conditions, reduce ATP consumption, and promote ATP synthesis
.
AMPK consists of
the catalytic subunit AMPKα, the scaffold protein AMPKβ and the regulatory subunit AMPKγ.
The CBS domain of AMPKγ can bind ATP, AMP, ADP, and change the conformation according to its proportions, thereby regulating AMPKα activity
.
On November 15, 2022, the team of Professor Zhao Bin and Professor Feng Xinhua of the Institute of Life Sciences of Zhejiang University, and the team of Tan Minjia, a researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, published an online report entitled Energy sensor AMPK gamma regulates translation via phosphatase PPP6C independent of Molecular Cell Research paper
by AMPK alpha.
By comparing the phosphorylation levels of substrates in AMPKγ and AMPKα knockout cells, using tandem affinity purification and phosphorylated proteomic analysis, AMPKγ revealed that AMPKγ can regulate phosphatase PPP6C, independently of the classical catalytic subunit AMPKα, and then regulate phosphorylation of its downstream substrates (e.
g.
, eEF2), thereby mediating the regulation
of protein synthesis at cellular energy levels.
by AMPK alpha.
By comparing the phosphorylation levels of substrates in AMPKγ and AMPKα knockout cells, using tandem affinity purification and phosphorylated proteomic analysis, AMPKγ revealed that AMPKγ can regulate phosphatase PPP6C, independently of the classical catalytic subunit AMPKα, and then regulate phosphorylation of its downstream substrates (e.
g.
, eEF2), thereby mediating the regulation
of protein synthesis at cellular energy levels.
In this study, by comparing the difference in phosphorylation levels of classical downstream substrates in AMPKγ and AMPKα knockout cells after glucose starvation treatment, it was found that phosphorylation of eEF2 proteins, which is thought to be regulated by AMPKα kinase, decreases after AMPKγ knockout, but rises
after AMPKγ knockout.
Further studies have shown that AMPKγ is able to participate in regulating the dephosphorylation
of eEF2.
Through the identification of AMPKγ interaction protein profiling and phosphatase library screening, it was found that PPP6C knockdown obviously led to increased eEF2 phosphorylation and could be regulated
by glucose starvation.
In vitro and in vivo results showed that energy levels could regulate the binding of AMPKγ to PPP6C, and in turn to the binding
of PPP6C to eEF2.
The results showed that AMPKγ could form a complex with PPP6C independently of AMPKα, sense energy changes, and regulate protein dephosphorylation
.
Quantitative phosphorylation modification omics in combination with the quantitative phosphorylation modification omics strategy of intracellular stable isotope labeling culture (SILAC) showed that in addition to eEF2, multiple phosphorylation sites were regulated
by similar mechanisms.
Further validation showed that glucose starvation can also regulate phosphorylation
of HSPB1 (S82) and PCM1 (S93) through AMPKγ-PPP6C.
after AMPKγ knockout.
Further studies have shown that AMPKγ is able to participate in regulating the dephosphorylation
of eEF2.
Through the identification of AMPKγ interaction protein profiling and phosphatase library screening, it was found that PPP6C knockdown obviously led to increased eEF2 phosphorylation and could be regulated
by glucose starvation.
In vitro and in vivo results showed that energy levels could regulate the binding of AMPKγ to PPP6C, and in turn to the binding
of PPP6C to eEF2.
The results showed that AMPKγ could form a complex with PPP6C independently of AMPKα, sense energy changes, and regulate protein dephosphorylation
.
Quantitative phosphorylation modification omics in combination with the quantitative phosphorylation modification omics strategy of intracellular stable isotope labeling culture (SILAC) showed that in addition to eEF2, multiple phosphorylation sites were regulated
by similar mechanisms.
Further validation showed that glucose starvation can also regulate phosphorylation
of HSPB1 (S82) and PCM1 (S93) through AMPKγ-PPP6C.
In summary, this study proposes for the first time that AMPKγ can participate in the regulation
of energy balance independently of AMPKα and other effector molecules (such as PPP6C).
AMPKγ-PPP6C-regulated protein dephosphorylation may also play an important role
in diseases related to energy stress disorders.
of energy balance independently of AMPKα and other effector molecules (such as PPP6C).
AMPKγ-PPP6C-regulated protein dephosphorylation may also play an important role
in diseases related to energy stress disorders.
Zhou Qi, Zhao Bin's research group, Institute of Life Sciences, Zhejiang University, and Hao Bingbing, Tan Minjia's research group, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, are co-first authors
of this paper.
Professor Zhao Bin, Professor Tan Minjia and Professor Feng Xinhua are co-corresponding authors
.
The work has also received strong support
from Chen Shuai, Ye Cunqi and other cooperative laboratories.
of this paper.
Professor Zhao Bin, Professor Tan Minjia and Professor Feng Xinhua are co-corresponding authors
.
The work has also received strong support
from Chen Shuai, Ye Cunqi and other cooperative laboratories.
Full text link:
Cellular energy levels regulate protein synthesis patterns by AMPKγ-PPP6C
(Contributing department: Tan Minjia Research Group)
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