mPPases create a conserved anionic membrane fingerprint as identified via multi-scale simulations
Alexandra O M Holmes1, Adrian Goldman1,2, Antreas C Kalli3
1School of Biomedical Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.
Abstract:
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.
Insights
Membrane-integral pyrophosphatases (mPPases) are crucial enzymes. New simulations reveal specific anionic lipid interactions at four sites, potentially key to mPPase function and stability.
Area of Science:
- Biochemistry
- Molecular Biology
- Biophysics
Background:
- Membrane-integral pyrophosphatases (mPPases) are vital membrane-bound enzymes.
- They hydrolyze inorganic pyrophosphate and translocate cations, impacting parasite infectivity and plant development.
- Emerging evidence suggests the membrane environment significantly influences mPPase function.
Purpose of the Study:
- To investigate the role of the membrane environment in mPPase mechanism.
- To identify specific lipid interactions with mPPases using advanced simulation techniques.
Main Methods:
- Multiscale molecular dynamics simulations were employed.
- Simulations were performed on mPPases from Thermotoga maritima, Vigna radiata, and Clostridium leptum.
Main Results:
- Specific anionic lipid interactions were identified at four distinct sites on mPPases.
- These interactions occur at both distal and interfacial regions of the protein.
- Conserved interactions involve positively charged residues on specific helices (1-4 for distal, 9-14 for interfacial).
Conclusions:
- Anionic lipid interactions are a conserved feature of mPPases.
- These interactions likely play a critical role in protein stability and function.
- Findings provide a basis for future structural and functional studies of mPPases.
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