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Fine-tuning pH sensor H98 by remote essential residues in the hydrogen-bond network of mTASK-3.
Fan, Xueming; Ye, Yifei; Saha, Aakash; Peng, Li; Pindi, Chinmai; Wang, Qi; Yang, Linghui; Liu, Jin; Tang, Xiangdong; Palermo, Giulia; Liao, Jiayu; Xu, Tingting; Lu, Yongzhi; Du, Guizhi.
Afiliación
  • Fan X; Department of Pain Management, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chen
  • Ye Y; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610000, China; Department of Anesthesiology, West China Hospital of Sichuan University, Cheng
  • Saha A; Department of Bioengineering, University of California Riverside, 900 University Avenue, Riverside, CA 92521, United States.
  • Peng L; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610000, China.
  • Pindi C; Department of Bioengineering, University of California Riverside, 900 University Avenue, Riverside, CA 92521, United States.
  • Wang Q; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610000, China; Department of Anesthesiology, West China Hospital of Sichuan University, Cheng
  • Yang L; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610000, China.
  • Liu J; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610000, China; Department of Anesthesiology, West China Hospital of Sichuan University, Cheng
  • Tang X; Sleep Medicine Center, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, C
  • Palermo G; Department of Bioengineering, University of California Riverside, 900 University Avenue, Riverside, CA 92521, United States.
  • Liao J; Department of Bioengineering, University of California Riverside, 900 University Avenue, Riverside, CA 92521, United States; Huaxi-Cal Research Center for Predictive Intervention Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan 610000, China.
  • Xu T; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guizhou, Guangdong 510530, China.
  • Lu Y; Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510005, China. Electronic address: lu_yongzhi@gzlab.ac.cn.
  • Du G; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610000, China; Department of Anesthesiology, West China Hospital of Sichuan University, Cheng
Int J Biol Macromol ; 273(Pt 2): 132892, 2024 Jul.
Article en En | MEDLINE | ID: mdl-38878921
ABSTRACT
TASK-3 generates a background K+ conductance which when inhibited by acidification depolarizes membrane potential and increases cell excitability. These channels sense pH by protonation of histidine residue H98, but recent evidence revealed that several other amino acid residues also contribute to TASK-3 pH sensitivity, suggesting that the pH sensitivity is determined by an intermolecular network. Here we use electrophysiology and molecular modeling to characterize the nature and requisite role(s) of multiple amino acids in pH sensing by TASK-3. Our results suggest that the pH sensor H98 and consequently pH sensitivity is influenced by remote amino acids that function as a hydrogen-bonding network to modulate ionic conductivity. Among the residues in the network, E30 and K79 are the most important for passing external signals near residue S31 to H98. The hydrogen-bond network plays a key role in selectivity or pH sensing in mTASK-3, and E30 and S31 in the network can modulate the conductive properties (E30) or reverse the pH sensitivity and selectivity of the channel (S31). Molecular dynamics simulations and pK1/2 calculation revealed that double mutants involving H98 + S31 primarily regulate the structure stability of the pore selectivity filter and pore loop regions, further strengthen the stability of the cradle suspension system, and alter the ionization state of E30 and K79, thereby preventing pore conformational change that normally occurs in response to varying extracellular pH. These results demonstrate that crucial residues in the hydrogen-bond network can remotely tune the pH sensing of mTASK-3 and may be a potential allosteric regulatory site for therapeutic molecule development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Canales de Potasio de Dominio Poro en Tándem / Simulación de Dinámica Molecular / Enlace de Hidrógeno Límite: Animals / Humans Idioma: En Revista: Int J Biol Macromol Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Canales de Potasio de Dominio Poro en Tándem / Simulación de Dinámica Molecular / Enlace de Hidrógeno Límite: Animals / Humans Idioma: En Revista: Int J Biol Macromol Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos