Evidence for major structural changes in subunit C of the vacuolar ATPase due to nucleotide binding

Armbrüster, Andrea; Hohn, Christina; Hermesdorf, Anne; Schumacher, Karin; Börsch, Michael; Grüber, Gerhard

doi:10.1016/j.febslet.2005.02.042

Cited by 59 publications

(62 citation statements)

References 35 publications

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“…Further complicating the understanding of this mechanism are the number of cellular binding partners for subunits likely to be involved in enzyme regulation. Subunit C, for example, has been shown to interact with kinases (47,50), actin (51), ATP (52), and the Regulator of the H ϩ -ATPase of vacuoles and endosomal membranes complex (53). Interestingly, the C subunit x-ray crystal structure was solved in two different conformations, but it remains unclear whether these changes may be linked to release of subunit C from the enzyme during regulated disassembly (18).…”

Section: Discussionmentioning

confidence: 99%

Subunit Interactions at the V1-Vo Interface in Yeast Vacuolar ATPase

Oot

Wilkens

2012

Journal of Biological Chemistry

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Background:The activity of the proton pumping vacuolar ATPase is regulated by reversible enzyme dissociation. Results: The ATPase and proton channel domains are held together by several intermediate affinity interactions. Conclusion: Intermediate affinity subunit-subunit interactions may play an important role in reversible enzyme dissociation. Significance: Targeting subunit-subunit interactions may be a means of modulating aberrant V-ATPase activity involved in human disease.

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Section: Discussionmentioning

confidence: 99%

Subunit Interactions at the V1-Vo Interface in Yeast Vacuolar ATPase

Oot

Wilkens

2012

Journal of Biological Chemistry

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“…According to Grüber et al subunit C is intimately involved in the reversible dissociation of the V0 and V1 domains. The nucleotide occupation of this latter and the conformational change in its structure allow such a dissociation (66,67).…”

Section: Importance Of C Subunitmentioning

confidence: 99%

Role of V-ATPases in solid tumors: Importance of the subunit C (Review)

Pérez-Sayáns¹

2009

Int J Oncol

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Abstract. Acidity is one of the main characteristics of OSCC (oral squamous cell carcinoma) as a solid tumor. The VATPase is the primary regulator of the tumor microenvironment, by means of proton extrusion to the extracellular medium. The decrease in extracellular pH confers the cells a resistant, highly invasive and metastatic phenotype. However, the acid medium confers an optimum pH to the degradative enzymes (such as proteases and MMPs) for their proper functioning. The C subunit (ATP6V1C) of V1 intra-membrane domain of the V-ATPase, is primarily responsible for its enzymatic function, through the control of a reversible dissociation of V0 and V1 domains. In this review, we describe the importance of V-ATPases in the control of tumor microenvironment, the potential strategies as protein targeting to improve the effectiveness of drug treatment and the role of the C subunit as the primarily responsible of the enzymatic control. The inhibition of the V-ATPase activity through PPIs (proton inhibitors) seems to reduce the destructive and metastatic capacity in tumors, such as hepatocellular carcinoma. Nevertheless, none of these inhibitors was proven to be useful in OSCC; therefore, it is highly important to carry out further studies in order to develop specific inhibitors of the C subunit, to control the devastating effects of OSCC. IntroductionThe main characteristics of the solid tumors (such as oral cancer) are the acidity and hypoxia, phenomena that result from the progression of metastatic cancer (1), the sensitivity to chemotherapeutic agents (2) and proliferation (3). In fact, a mechanism of resistance to cytotoxic drugs is the alteration of the pH gradient between the extracellular environment and cell cytoplasm (4).The cytosolic pH seems to be strictly regulated by four mechanisms: the family of sodium-proton exchangers (NHE), the family of bicarbonate transporters (BCT), the family of monocarboxylate transporters (MCT) and the proton pumps (ATPase) (5,6) ( Fig. 1). The lactate production has been commonly seen as the first acidification mechanism of the microenvironment (7). The lactate accumulation results in the activation of the aerobic glycolytic metabolism (8) which increases the amount of cellular lactate that is transported outside the cell through the H + /lactate co-transporter (MCT) (9). The increase in aerobic glycolysis (8,10) provides to the tumor a metabolic environment characterized by low levels of serum, hypoxia and an acid extracellular pH. This microenvironment increases the invasive ability of the tumor and the expression of growth and angiogenic factors/receivers (11). All this is correlated to an increment of the intracellular pH, an aggravation of the initial development of the interstitial acid microenvironment and a reversed transmembrane pH gradient (11,12). This increase in the intracellular pH is concomitant with an increment of DNA synthesis (8,13,14), cell cycle progression (15-17), serum and substrate-independent growth (8) and the in vivo growth of the tumor (8,18) and ...

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Section: The C Subunitmentioning

confidence: 99%

“…According to Grüber (2005) and Armbruster et al (2005), this subunit is intimately involved in the reversible dissociation of the V1 and V0 domains. The dissociation is possible due to the occupation of the subunit by nucleotides and conformational changes in the structure of the subunit (Gruber, 2005;Armbruster et al, 2005). In addition to establishing the crystalline structure of the C subunit and its importance in reversible dissociation as a control mechanism of V-ATPase activity, Forgac (2007) described the relationship between the C subunit and the E and G subunits of the V1 domain and the a subunit of the V0 domain, and concluded that the C subunit was the primary mechanism responsible for enzyme control (Forgac, 2007;.…”

Section: The C Subunitmentioning

confidence: 99%

An update in the structure, function, and regulation of V-ATPases: the role of the C subunit

et al. 2012

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Vacuolar ATPases (V-ATPases) are present in specialized proton secretory cells in which they pump protons across the membranes of various intracellular organelles and across the plasma membrane. The proton transport mechanism is electrogenic and establishes an acidic pH and a positive transmembrane potential in these intracellular and extracellular compartments. V-ATPases have been found to be practically identical in terms of the composition of their subunits in all eukaryotic cells. They have two distinct structures: a peripheral catalytic sector (V1) and a hydrophobic membrane sector (V0) responsible for driving protons. V-ATPase activity is regulated by three different mechanisms, which control pump density, association/dissociation of the V1 and V0 domains, and secretory activity. The C subunit is a 40-kDa protein located in the V1 domain of V-ATPase. The protein is encoded by the ATP6V1C gene and is located at position 22 of the long arm of chromosome 8 (8q22.3). The C subunit has very important functions in terms of controlling the regulation of the reversible dissociation of V-ATPases.Keywords:V-ATPases, proton transport, ATP6V1C1,V1 domain, V0 domain, C subunit. Uma atualização na estrutura, função e regulação das V-ATPases:o papel das subunidades C ResumoAs Vacuolar ATPases (V-ATPases) estão presentes nas células especializadas em secreção de protões, nas quais eles são bombeados através das membranas de vários organelos intracelulares e da membrana plasmática. O mecanismo de transporte de protões é eletrogênico e estabelece um pH ácido e um potencial transmembrana positivo nestes compartimentos intracelulares e extracelulares. As V-ATPases foram encontradas em todas as células eucarióticas, praticamente idênticas em termos de composição das suas subunidades. Elas têm duas estruturas distintas: um setor periférico catalítico (V1) e uma membrana hidrofóbica (V0), responsável pela condução de protões. A atividade das V-ATPases é regulada por três mecanismos diferentes, os quais controlam a densidade de bomba, associação/dissociação de domínios V1 e V0, e a atividade secretora. A subunidade C é uma proteína de 40-kDa, localizada no domínio V1 da V-ATPase. Essa proteína é codificada pelo gene ATP6V1C e está localizada na posição 22 do braço longo do cromossomo 8 (8q22.3). A subunidade C tem funções muito importantes em termos de controle do regulamento da dissociação reversível da V-ATPase.Palavras-chave: V-ATPases, transporte de protões, ATP6V1C1, domínio V1, domínio V0, subunidade C.

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Evidence for major structural changes in subunit C of the vacuolar ATPase due to nucleotide binding

Cited by 59 publications

References 35 publications

Subunit Interactions at the V1-Vo Interface in Yeast Vacuolar ATPase

Subunit Interactions at the V1-Vo Interface in Yeast Vacuolar ATPase

Role of V-ATPases in solid tumors: Importance of the subunit C (Review)

An update in the structure, function, and regulation of V-ATPases: the role of the C subunit

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