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Eukaryotic V-ATPase and Its Super-complexes: From Structure and Function to Disease and Drug Targeting

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Regulation of Ca2+-ATPases,V-ATPases and F-ATPases

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 14))

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.

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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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Authors and Affiliations

  1. Kadmon Corporation, Molecular Signaling, Alexandria Center for Life Science, 450 East 29th Street, New York, NY, 10016, USA

    Vladimir Marshansky

  2. Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Simches Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA

    Vladimir Marshansky

  3. Department of Medicine, Harvard Medical School, Boston, MA, 02114, USA

    Vladimir Marshansky

  4. Department of Biochemistry, Faculty of Pharmaceutical Sciences, Iwate Medical University, Iwate, 028-3694, Japan

    Masamitsu Futai

  5. Institute of Scientific and Industrial Research, Osaka University, Osaka, 567-0047, Japan

    Masamitsu Futai

  6. School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Republic of Singapore

    Gerhard GrĂ¼ber

  7. Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore, 138671, Republic of Singapore

    Gerhard GrĂ¼ber

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  1. Vladimir Marshansky
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  2. Masamitsu Futai
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  3. Gerhard GrĂ¼ber
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Correspondence to Vladimir Marshansky .

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  1. Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. University of Manitoba, Institute of Cardiovascular Science St. Boniface Hospital Research, Winnipeg, Manitoba, Canada

    Naranjan S Dhalla

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© 2016 Springer International Publishing Switzerland

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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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