# Structure and regulation of the vacuolar ATPase

> **NIH NIH R01** · UPSTATE MEDICAL UNIVERSITY · 2020 · $338,062

## Abstract

Project Summary
 The proton-pumping vacuolar ATPase (V-ATPase; V1Vo-ATPase) is an essential enzyme complex found
in the endomembrane system of all eukaryotic organisms and in the plasma membrane of some animal cells.
The V-ATPase functions in ATP hydrolysis-driven acidification of subcellular compartments or the extracellular
space, a process vital for basic cellular processes including endocytosis, protein trafficking, bone remodeling,
urine acidification, sperm maturation, and neurotransmitter release. Loss of V-ATPase in animal cells is
embryonic lethal, while partial loss of function (or hyperactivity) has been linked to numerous human diseases,
such as renal tubular acidosis, osteoporosis, diabetes, male infertility, neurodegeneration, cancer, and AIDS.
Fighting these diseases on a molecular level will require a detailed understanding of the structure, catalytic
mechanism, and regulation of the eukaryotic V-ATPase complex.
 In cells, V-ATPase activity is regulated by a unique mechanism referred to as reversible disassembly, a
condition under which the complex dissociates into V1-ATPase and Vo proton channel sectors that are both
functionally silenced. Despite its important role in V-ATPase function, the molecular mechanism of activity
regulation by reversible disassembly is poorly understood, a gap in knowledge that is largely due to the lack of
high-resolution structural information and a defined in vitro model system to study the process under controlled
conditions.
 The immediate goal of this project is to obtain high-resolution structural and mechanistic information
aimed at a better understanding of V-ATPase regulation and to uncover non-canonical functions of the V-
ATPase Vo membrane sector that may play a role in neuronal communication. We will address these questions
with the following specific aims:
(1) Molecular determinants of V-ATPase assembly and disassembly
(2) Non-canonical functions of the V-ATPase Vo membrane sector.
 We study the structure and regulation of the yeast V-ATPase, a powerful model system for the
mammalian enzyme due to the high level of conservation of the enzyme's structure and mechanism across
species, the ease of genetic manipulation, and the ability to obtain highly purified enzyme with a defined
subunit composition. The long-term objective of the project is to develop strategies aimed at either promoting
or inhibiting the process of reversible disassembly of the human V-ATPase that will allow modulation of the
activity of the enzyme in a tissue and subunit isoform dependent manner for therapeutic purposes.

## Key facts

- **NIH application ID:** 9982337
- **Project number:** 5R01GM058600-17
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** Stephan Wilkens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,062
- **Award type:** 5
- **Project period:** 1999-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982337

## Citation

> US National Institutes of Health, RePORTER application 9982337, Structure and regulation of the vacuolar ATPase (5R01GM058600-17). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9982337. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*