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Structure of the hexameric fungal plasma membrane proton pump in its autoinhibited state

Sabine Heit1, Maxwell M G Geurts1, Bonnie J Murphy2

  • 1Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.

Science Advances
|November 10, 2021
PubMed

Insights

The fungal H+-ATPase Pma1 forms hexamers, crucial for nutrient uptake. This study reveals the structure of these hexamers, explaining their autoinhibition and providing a basis for drug development.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Mycology

Background:

  • The fungal plasma membrane H+-ATPase Pma1 generates proton-motive force essential for nutrient import.
  • Pma1 exists as autoinhibited hexamers in starving fungi, activated by glucose and phosphorylation.
  • Oligomerization of related P-type ATPases is not known, making Pma1 hexamer relevance unclear.

Purpose of the Study:

  • Determine the structure of hexameric Pma1 from *Neurospora crassa*.
  • Elucidate the molecular basis of hexamer formation and autoinhibition.
  • Provide a foundation for structure-based drug development targeting Pma1.

Main Methods:

  • Electron cryo-microscopy (3.3-Å resolution).
  • Coarse-grained molecular dynamics simulations in a lipid bilayer.

Main Results:

  • The structure of hexameric Pma1 was determined.
  • Molecular basis for hexamer formation and autoinhibition elucidated.
  • Simulations suggest lipid-mediated contacts and protein-induced membrane deformation.

Conclusions:

  • Hexamization is a key feature of fungal Pma1, regulating its activity.
  • The determined structure offers insights into Pma1 function and potential drug targets.
  • Membrane interactions play a role in Pma1 hexamer function, potentially aiding proton transport.

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