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Related Concept Videos

ATP Driven Pumps III: V-type Pumps01:30

ATP Driven Pumps III: V-type Pumps

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V-type pumps are ATP-driven pumps found in the vacuolar membranes of plants, yeast, endosomal and lysosomal membranes of animal cells, plasma membranes of a few specialized eukaryotic cells, and some prokaryotes. They are also known as the V1Vo-ATPase, that couple ATP hydrolysis to transport protons against a concentration gradient.
The peripheral or cytosolic V1 domain with eight subunits is involved in ATP hydrolysis. The integral or transmembrane V0 domain containing at least five subunits...
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ATP Synthase: Mechanism01:48

ATP Synthase: Mechanism

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In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
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ATP Driven Pumps I: An Overview01:27

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ATP-driven pumps, also known as transport ATPases, are integral membrane proteins. They have binding sites for ATP located on the membrane's cytosolic side and the ion-conducting domain in the transmembrane region. These pumps use the free energy released from ATP hydrolysis to move the solutes across cell membranes against an electrochemical gradient.
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and...
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Allosteric Proteins-ATCase01:19

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Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
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ATP Driven Pumps II: P-type Pumps01:34

ATP Driven Pumps II: P-type Pumps

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The P-type pumps are a large family of integral membrane transporter ATPases. They are divided into five major types based on substrate specificity, from I to V.
A typical P-type pump has three cytosolic domains: nucleotide-binding (N), phosphorylation (P), and activator (A) domains. These domains are connected to the membrane-spanning helices by short amino acid segments. ATP hydrolysis and covalent phosphoenzyme intermediate formation are crucial parts of the catalytic cycle. At the highly...
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Regulation of Metabolism01:19

Regulation of Metabolism

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Cellular needs and conditions vary from cell to cell and change within individual cells over time. For example, the required enzymes and energetic demands of stomach cells are different from those of fat storage cells, skin cells, blood cells, and nerve cells. Furthermore, a digestive cell works much harder to process and break down nutrients during the time that closely follows a meal compared with many hours after a meal. As these cellular demands and conditions vary, so do the amounts and...
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Measuring In Vitro ATPase Activity for Enzymatic Characterization
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Small-Molecule Modulators of the ATPase VCP/p97 Affect Specific p97 Cellular Functions.

Ainoa Figuerola-Conchas1,2, Jacques Saarbach1,2, Jean-Pierre Daguer2,3

  • 1Department of Cell Physiology and Metabolism , University of Geneva , 1211 Geneva 4 , Switzerland.

ACS Chemical Biology
|December 3, 2019
PubMed
Summary
This summary is machine-generated.

Researchers discovered two new compounds, NW1028 and NW1030, that target the regulatory domain of VCP/p97 (Valosin-containing protein/p97) without causing cell death. These molecules reveal p97

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Area of Science:

  • Molecular and Cellular Biology
  • Biochemistry
  • Chemical Biology

Background:

  • Valosin-containing protein (VCP), also known as p97, is an AAA+ ATPase crucial for cellular processes like protein homeostasis and cell division.
  • Existing VCP/p97 inhibitors target the main ATPase domain, leading to cell death, limiting their therapeutic potential.
  • The regulatory domain of VCP/p97, comprising N-terminal and D1 ATPase domains, presents an alternative target for modulating its function.

Purpose of the Study:

  • To identify novel small molecules targeting the regulatory domain of VCP/p97.
  • To characterize the mechanism of action and cellular effects of these new compounds.
  • To explore the role of VCP/p97 in specific cellular processes, such as mitotic spindle orientation.

Main Methods:

  • Utilized PNA-encoded chemical libraries for high-throughput screening.
  • Performed ATPase assays to assess the catalytic activity of VCP/p97 in the presence of compounds.
  • Employed photoaffinity labeling to map the binding site of the identified small molecules.
  • Investigated the impact of compounds on VCP/p97-dependent reporter degradation and mitotic spindle orientation in HeLa cells.

Main Results:

  • Identified two novel small molecules, NW1028 and NW1030, that bind to the regulatory domain of VCP/p97.
  • NW1028 inhibits a VCP/p97-dependent reporter degradation, while NW1030 increases it, indicating distinct functional modulation.
  • ATPase assays confirmed that NW1028 and NW1030 do not inhibit the main catalytic ATPase domain of VCP/p97.
  • Photoaffinity labeling mapped the binding site to a cleft between the N-terminal and D1 ATPase domains.
  • Demonstrated a role for VCP/p97 in regulating mitotic spindle orientation in HeLa cells using these compounds.

Conclusions:

  • Discovered two unique small molecules, NW1028 and NW1030, that selectively target the regulatory domain of VCP/p97.
  • These compounds offer a new avenue for modulating VCP/p97 functions without inducing general cytotoxicity.
  • The study reveals a novel function for VCP/p97 in the regulation of mitotic spindle orientation, elucidated through the use of these specific inhibitors.