Abstract
The eukaryotic vacuolar-type ATPase (V-ATPase) is a multi-subunit membrane protein complex, which is evolutionarily conserved from yeast to human. It is also functionally conserved and operates as a rotary proton pumping nano-motor. In the first part of this chapter we discuss the structure and function of the yeast V-ATPase (V1VO) holoenzyme, We focus on the structural features of its subunits forming both catalytic V1 and proton conducting VO sectors. Particularly, the recently solved structure of DF-subunit complex is discussed in relation to the energy coupling and regulation of yeast V-ATPase. It is noteworthy that the structure could contribute to understanding the function and regulation of V-ATPases of eukaryotes including human, leading to the rational design of specific inhibitors for medical applications. In addition to the well characterized role as proton pump, V-ATPases have acquired alternative cellular functions during evolution. In the second part we analyze novel roles of V-ATPase in function, signaling, and vesicular trafficking of cellular receptors. Our recent studies have uncovered that V-ATPase itself functions as an evolutionarily conserved pH-sensing and signaling receptor, which forms super-complex with aldolase/cytohesin-2/Arf1,6 small GTPases in early endosomes. On the other hand, V-ATPase forms a super-complex with mTORC1/Ragulator/Rag/Rheb small GTPases in late endosome/lysosomes and is involved in amino-acids sensing and monitoring nutritional state of cells. Finally, we discuss the role of V-ATPase in the development and progression of various diseases including cancer, diabetes, and osteopetrosis among others. We also present emerging approaches and future perspectives for specific drug targeting to V-ATPase and its super-complexes.
Keywords
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Abbreviations
- a2N:
-
N-terminal cytosolic tail of a2-subunit V-ATPase
- Arf1:
-
ADP-ribosylation factor 1
- Arf6:
-
ADP-ribosylation factor 6
- BafA1 :
-
bafilomycin A1
- c/c″-ring:
-
Ring composed by the c- and c″-subunits
- ConA :
-
concanamycin A
- CRP:
-
Calorie restriction pathway
- cryo-EM:
-
Cryo-Electron microscopy
- CTH2:
-
Cytohesin-2
- dErbB:
-
Dimeric EGFR/ErbB-receptor
- EGF:
-
Epidermal growth factor
- EmGFP:
-
Emerald green fluorescent protein
- FKPB12:
-
FK506/rapamycin binding protein
- FRET:
-
Fluorescence resonance energy transfer
- Fz:
-
Frizzled
- GH:
-
Growth hormone
- HRG-1:
-
Heme-responsive gene 1 protein
- IGF-1R:
-
Insulin-like growth factor-1 receptor
- IR:
-
Insulin receptor
- LRP6:
-
Low-density receptor-related protein
- M. sexta :
-
Manduca sexta
- mErbB:
-
Monomeric EGFR/ErbB-receptor
- mTORC1:
-
Mammalian target of rapamycin complex 1
- mTORC2:
-
Mammalian target of rapamycin complex 2
- NMR:
-
Nuclear magnetic resonance
- NOE:
-
Nuclear Overhauser effect
- PAT1:
-
Proton coupled amino acid transporter 1
- PI3K:
-
Phosphatidylinositol 3-kinase pathway
- PKA:
-
Protein kinase A
- PPI:
-
Protein–protein interaction interface inhibitors
- RagA/C:
-
Rag A/C GTPases
- Ragulator:
-
Ragulator complex
- Ras:
-
Rat sarcoma small GTPase
- RAVE:
-
Regulator of ATPase of vacuoles and endosomes
- Rbcn-3:
-
Rabconnectin-3A/B
- Rheb GTPase:
-
Ras homolog enriched in brain
- S. cerevisiae :
-
Saccharomyces cerevisiae
- SAXS:
-
Small-angle X-ray scattering
- ScDF1 and ScDF2:
-
Two conformations of subunit DF complex
- TFEB :
-
Transcription factor EB
- TSC complex:
-
Tuberous sclerosis complex
- V-ATPase:
-
V-type ATPase
- ΔpH:
-
Proton gradient
- ΔΨ:
-
Membrane potential
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Acknowledgements
Original work in the authors’ laboratories is supported by NIH DK038452, BADERC DK057521-08 (Marshansky), Ministry of Education Tier 2 (MOE2011-T2-2-156; ARC 18/12), Singapore (GrĂ¼ber), and Japan Science and Technology Agency (Futai).
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Marshansky, V., Futai, M., GrĂ¼ber, G. (2016). Eukaryotic V-ATPase and Its Super-complexes: From Structure and Function to Disease and Drug Targeting. In: Chakraborti, S., Dhalla, N. (eds) Regulation of Ca2+-ATPases,V-ATPases and F-ATPases. Advances in Biochemistry in Health and Disease, vol 14. Springer, Cham. https://doi.org/10.1007/978-3-319-24780-9_16
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