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Introduction to v-ATPase

 The v-ATPase, also known as vacuolar-type ATPase, is a multisubunit enzyme complex found in the membranes of various cellular compartments, including lysosomes, endosomes, Golgi apparatus, and secretory vesicles. It plays a crucial role in the regulation of intracellular pH and the acidification of these compartments. 

Structure of V-ATPase.
ATP6V0c ATP6V0A1 ATP6V1A ATP6ap2

Structure

The v-ATPase is composed of two main domains: the V1 domain, located in the cytosol, and the V0 domain, embedded in the membrane. 


The V1 domain is responsible for ATP hydrolysis, while the V0 domain functions as a proton pump.


The V1 domain consists of eight different subunits (A-H), which form a peripheral complex resembling a rotary motor. Subunits A and B are involved in ATP hydrolysis, whereas subunits C, D, and E are involved in ATP binding and subunit assembly. Subunits F, G, and H are regulatory subunits that participate in the assembly and regulation of the complex.


The V0 domain consists of another set of subunits (a, c, c', c", d, and e), which are integral membrane proteins. Subunit a is involved in proton translocation, while the c subunits form a ring-like structure that transports protons across the membrane. Subunits d and e are required for the stability and assembly of the complex.

                        Sun-Wada & Wada (2015), BBA 

Function

The v-ATPase functions primarily as a proton pump, using the energy derived from ATP hydrolysis to transport protons (H+) across the membrane against their concentration gradient. This process leads to the acidification of the compartment, creating an acidic environment necessary for various cellular processes. Some important functions of the v-ATPase include:  


  • Acidification of lysosomes and endosomes: The v-ATPase plays a vital role in the acidification of these compartments, enabling the degradation of cellular waste, recycling of molecules, and activation of enzymes involved in these processes.


  • Neurotransmitter storage and release: In synaptic vesicles of neurons, the v-ATPase acidifies the vesicles, allowing the packaging and storage of neurotransmitters. Upon stimulation, the v-ATPase regulates the release of neurotransmitters by modulating the pH-dependent fusion of vesicles with the plasma membrane.


  • Protein processing and trafficking: The v-ATPase participates in the processing and trafficking of proteins through the secretory pathway, including the Golgi apparatus. It influences protein glycosylation, sorting, and vesicle transport.


  • pH regulation and homeostasis: By acidifying various cellular compartments, the v-ATPase contributes to pH regulation and maintains the pH balance within the cell. This is essential for the proper functioning of enzymes, ion channels, and other cellular processes.

Illustration of  v-ATPase complex. Function and Regulation.

Collins & Forgac (2020), BBA

Regulation

The activity of the v-ATPase can be regulated through multiple mechanisms. One key regulatory mechanism involves reversible disassembly and reassembly of the V1 and V0 domains, which modulates the proton pump activity. Additionally, various factors such as pH, ATP availability, post-translational modifications, and binding of regulatory proteins can influence its activity.

Video from Rubinstein Laboratory @rubinsteinlaboratory2935

Overall

V-ATPase is a crucial enzyme complex responsible for proton pumping and acidification of cellular compartments. Its diverse functions make it essential for numerous cellular processes, including protein trafficking, neurotransmitter release, and pH regulation.

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