H+-ATPase (proton pump)
Ontology highlight
ABSTRACT:
SUBMITTER: 
David Nickerson
PROVIDER: 293 | Physiome Model Repository |
REPOSITORIES: PMR
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Project description:Mutations in the Microrchidia CW-Type Zinc Finger 2 (MORC2) GHKL ATPase module cause Charcot Marie Tooth type 2Z or a broad range of neuropathy, but etiology and therapeutic strategy are not fully defined. Previously, we reported that the Morc2a p.S87L mouse model led to neuropathy and muscular dysfunction through DNA damage accumulation. This study revealed that Morc2a p.S87L caused a protein synthesis defect, resulting in the loss of function of Morc2a and weakening its function of maintaining DNA integrity and hydroxyl radical scavenging in the GHKL ATPase domain. Morc2a GHKL ATPase domain was considered a therapeutic target based on its function of simultaneously complementing hydroxyl radical scavenging and ATPase activity. Adeno-associated virus PHP.eB serotype that has high central nervous system transduction efficiency was applied to express Morc2a or Morc2a GHKL ATPase domain protein in vivo. AAV gene therapy improved neuropathy and muscular dysfunction with single-time treatment. The loss of function characteristics due to protein synthesis defect in Morc2a p.S87L was also observed in human MORC2 p.S87L or p.R252W variant, suggesting a relevance between mouse and human pathogenesis. Here, we demonstrate Morc2a p.S87L variant causes hydroxyl radical-mediated neuropathy and could be rescued through AAV-based gene therapy.
2024-02-06 | GSE235918 | GEO
Project description:The general consensus is that the vacuolar-type H+-translocating ATPase (V-ATPase) is critical for macroautophagy/autophagy. However, there is a fundamental conundrum because follicular lymphoma-associated mutations in the V-ATPase result in lysosomal/vacuolar deacidification but elevated autophagy activity under nutrient-replete conditions and the underlying mechanisms remain mysterious. Here, working in yeast, we show that V-ATPase dysfunction activates a selective autophagy flux termed the "V-ATPase-autophagy axis". By combining transcriptomic and proteomic profiling, along with genome-wide suppressor screening approaches, we found that the V-ATPase-autophagy axis is regulated through a unique mechanism distinct from classical nitrogen starvation-induced autophagy. Tryptophan metabolism negatively regulates the V-ATPase-autophagy axis via two parallel effectors. On the one hand, it activates ribosome biogenesis, thus repressing the translation of the transcription factor Gcn4/ATF4. On the other hand, tryptophan fuels NAD+ de novo biosynthesis to inhibit autophagy. These results provide a clear explanation for the mutational activation of autophagy seen in follicular lymphoma patients.
2025-03-11 | GSE290977 | GEO
Project description:Cohesin stably holds together the sister chromatids from S phase until mitosis. To do so, cohesin must be protected against its cellular antagonist Wapl. Eco1 acetylates cohesinâs Smc3 subunit, which locks together the sister DNAs. We used yeast genetics to dissect how Wapl drives cohesin from chromatin and identified mutants of cohesin that are impaired in ATPase activity but remarkably confer robust cohesion that bypasses the need for the cohesin protectors Eco1 in yeast and Sororin in human cells. We uncover an unexpected functional asymmetry within the heart of cohesinâs highly conserved ABC-like ATPase machinery and show that an activity associated with one of cohesinâs two ATPase sites drives DNA release from cohesin rings. This key mechanism is conserved from yeast to humans. We propose that Eco1 locks cohesin rings around the sister chromatids by counteracting an asymmetric cohesin-associated ATPase activity. Effect of mutations in Smc1 and Smc3 on cohesin loading onto chromosomes
2016-02-18 | E-GEOD-76891 | biostudies-arrayexpress
Project description:Whole hearts from wild-type and Na,K-ATPase alpha 1 het. mice. Adult male, 8-16 weeks old on a 129/BSwiss background. Keywords: repeat sample
2004-11-19 | GSE1134 | GEO
Project description:Synaptic vesicles are organelles with a precisely defined protein and lipid composition, yet the molecular mechanisms for the biogenesis of synaptic vesicles are mainly unknown. Here, we discovered a well-defined interface between the synaptic vesicle V-ATPase and synaptophysin by in situ cryo-electron tomography and single particle cryo-electron microscopy of functional synaptic vesicles isolated from mouse brains. The synaptic vesicle V-ATPase is an ATP-dependent proton pump that establishes the protein gradient across the synaptic vesicle, which in turn drives the uptake of neurotransmitters. Synaptophysin and its paralogs synaptoporin and synaptogyrin belong to a family of abundant synaptic vesicle proteins whose function is still unclear. We performed structural and functional studies of synaptophysin knockout mice, confirming the identity of synaptophysin as an interaction partner with the V-ATPase. Although there is little change in the conformation of the V-ATPase upon interaction with synaptophysin, the presence of synaptophysin in synaptic vesicles profoundly affects the copy number of V-ATPases. This effect on the topography of synaptic vesicles suggests that synaptophysin assists in their biogenesis. In support of this model, we observed that synaptophysin knockout mice exhibit severe seizure susceptibility, suggesting an imbalance of neurotransmitter release as a physiological consequence of the absence of synaptophysin.
2024-06-04 | PXD052814 |
Project description:Cohesin stably holds together the sister chromatids from S phase until mitosis. To do so, cohesin must be protected against its cellular antagonist Wapl. Eco1 acetylates cohesin’s Smc3 subunit, which locks together the sister DNAs. We used yeast genetics to dissect how Wapl drives cohesin from chromatin and identified mutants of cohesin that are impaired in ATPase activity but remarkably confer robust cohesion that bypasses the need for the cohesin protectors Eco1 in yeast and Sororin in human cells. We uncover an unexpected functional asymmetry within the heart of cohesin’s highly conserved ABC-like ATPase machinery and show that an activity associated with one of cohesin’s two ATPase sites drives DNA release from cohesin rings. This key mechanism is conserved from yeast to humans. We propose that Eco1 locks cohesin rings around the sister chromatids by counteracting an asymmetric cohesin-associated ATPase activity.
2016-02-18 | GSE76891 | GEO
Project description:RNA quality control pathways serve to get rid of faulty RNAs and therefore must be able to discriminate these RNAs from those that are normal. Here we present evidence that the ATPase cycle of SF1 Helicase Upf1 is required for mRNA discrimination during Nonsense-Mediated Decay (NMD). Mutations affecting the Upf1 ATPase cycle disrupt the mRNA selectivity of Upf1, leading to indiscriminate accumulation of NMD complexes on both NMD target and non-target mRNAs. In addition, two modulators of NMD - translation and termination codon-proximal poly(A) binding protein - depend on Upf1 ATPase to limit Upf1-non-target association. Preferential ATPase-dependent dissociation of Upf1 from non-target mRNAs in vitro suggests that selective release of Upf1 contributes to the ATPase-dependence of Upf1 target discrimination. Given the prevalence of helicases in RNA regulation, ATP hydrolysis may be an underappreciated, yet widely employed, activity in target RNA discrimination. CLIP and RIP-seq against Wild Type and Mutant Upf1 in HEK293-T cell lines
2015-07-06 | E-GEOD-69584 | biostudies-arrayexpress