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ATP Synthase: Mechanism01:48

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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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Secretory vesicles, also known as dense core vesicles (DCVs), are membrane-bound vesicles that transport secretory proteins, such as hormones or neurotransmitters. Regulated secretory vesicles transport proteins from the trans-Golgi network to the exterior of the cell. Proteins present in regulated secretory vesicles are required to be rapidly exocytosed in large amounts upon a specific stimulus.
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ATP synthase or ATPase is among the most conserved proteins found in bacteria, mammals, and plants. This enzyme can catalyze a forward reaction in response to the electrochemical gradient, producing ATP from ADP and inorganic phosphate. ATP synthase can also work in a reverse direction by hydrolyzing ATP and generating an electrochemical gradient. Different forms of ATP synthases have evolved special features to meet the specific demands of the cell. Based on their specific feature, ATP...
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Related Experiment Video

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In Vivo Single-Molecule Tracking at the Drosophila Presynaptic Motor Nerve Terminal
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Syntaxin binding mechanism and disease-causing mutations in Munc18-2.

Yvonne Hackmann1, Stephen C Graham, Stephan Ehl

  • 1Cambridge Institute for Medical Research, University of Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0XY, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|November 7, 2013
PubMed
Summary

Mutations in Munc18-2 cause FHL5. This study reveals Munc18-2

Keywords:
immunodeficiencymembrane traffickingsecretory lysosomes

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Area of Science:

  • Immunology
  • Molecular Biology
  • Structural Biology

Background:

  • Mutations in syntaxin 11 (Stx11) or Munc18-2 lead to familial hemophagocytic lymphohistiocytosis (FHL4/FHL5) by impairing cytotoxic T lymphocyte (CTL) and natural killer (NK) cell cytotoxicity.
  • The molecular mechanisms of Munc18-2 and Stx11 interaction specificity and IL-2 mediated compensation of cytotoxicity remain unclear.

Purpose of the Study:

  • To elucidate the structural basis of Munc18-2 and Stx11 interaction.
  • To understand how mutations in Munc18-2 cause disease.
  • To investigate the mechanisms of cytotoxicity restoration in IL-2 activated cells.

Main Methods:

  • Determined the crystal structure of human Munc18-2 at 2.6 Å resolution.
  • Mapped 18 point mutations onto the Munc18-2 structure.
  • Assessed binding affinities of Munc18-2 to Stx11 and Stx3.

Main Results:

  • Four disease-associated Munc18-2 mutations (R39P, L130S, E132A, P334L) are located at syntaxin and SNARE binding interfaces.
  • Munc18-2 exhibits a ~20-fold higher binding affinity for Stx11 compared to Stx3, indicating specific binding.
  • IL-2 activation increases Stx3 levels, promoting Munc18-2 binding in the absence of Stx11, and Munc18-1 can bind Stx11 in activated CTLs.

Conclusions:

  • Structural and binding data provide insights into Munc18-2's selective interaction with Stx11.
  • Increased Stx3 levels upon IL-2 activation can compensate for Stx11 deficiency.
  • Munc18-1 can substitute for Munc18-2 in binding Stx11 in IL-2 activated CTLs, explaining cytotoxicity restoration.