4.6 Article

mPPases create a conserved anionic membrane fingerprint as identified via multi-scale simulations

Journal

PLOS COMPUTATIONAL BIOLOGY
Volume 18, Issue 10, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pcbi.1010578

Keywords

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Funding

  1. Biotechnology and Biological Sciences Research Council (BBSRC) DTP fellowship [BB/M011151/1]
  2. BBSRC [BB/T006048/1]
  3. Academy of Finland [1322609]
  4. Engineering and Physical Sciences Research Council (EPSRC) [EP/R029407/1]

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In this study, we demonstrated for the first time that membrane-integral pyrophosphatases (mPPases) form specific anionic lipid interactions at specific sites. These interactions are important for protein stability and function, and may play a crucial role in future research.
Membrane-integral pyrophosphatases (mPPases) are membrane-bound enzymes responsible for hydrolysing inorganic pyrophosphate and translocating a cation across the membrane. Their function is essential for the infectivity of clinically relevant protozoan parasites and plant maturation. Recent developments have indicated that their mechanism is more complicated than previously thought and that the membrane environment may be important for their function. In this work, we use multiscale molecular dynamics simulations to demonstrate for the first time that mPPases form specific anionic lipid interactions at 4 sites at the distal and interfacial regions of the protein. These interactions are conserved in simulations of the mPPases from Thermotoga maritima, Vigna radiata and Clostridium leptum and characterised by interactions with positive residues on helices 1, 2, 3 and 4 for the distal site, or 9, 10, 13 and 14 for the interfacial site. Due to the importance of these helices in protein stability and function, these lipid interactions may play a crucial role in the mPPase mechanism and enable future structural and functional studies. Author summary In this work, we demonstrated conservation of lipid-interaction sites on proteins from two species that deviated from their evolutionary common ancestors a long time ago, using the membrane-integral pyrophosphatases from a thermophilic bacteria species and a plant species. We further showed that these sites are preserved in homology modelled proteins of the same family. This retention of a common lipid interaction profile or fingerprint and our ability to predict this for other proteins in this family may indicate that they are more integral to protein function than previously thought. By identifying lipid interactions that may act to stabilise the protein structure, these properties could be exploited to solve protein structures, and the interfacial site's potential involvement in inter-subunit communication may be useful for further investigation of the catalytic cycle of this clinically relevant membrane protein family.

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