The most abundant molecule in cell membranes is the lipid phosphatidylcholine (PC, commonly known as lecithin); accordingly, the enzymes responsible for synthesizing it are essential. Research published in the May 4 issue of the Journal of Biological Chemistry used computer simulations to gain insights into how one of these enzymes activates and shuts off PC production. These results could help researchers understand why small changes in this enzyme can lead to conditions like blindness and dwarfism.
Rosemary Cornell, a professor of molecular biology and biochemistry at Simon Fraser University in Canada, studies the enzyme CTP:phosphocholine cytidylyltransferase, or CCT. CCT sets the rate of PC production in cells by binding to cell membranes with low PC content.
CCT is a key enzyme that maintains a balanced composition of cell membrane phospholipids. Image highlights the dynamics of a portion of the enzyme CCT that is essential for regulation of its functions. The molecular dynamics was explored in a collaboration between the Cornell and Tieleman labs using computational methods.
Credit: Mohsen Ramezanpour and Jaeyong Lee
When bound to membranes, the CCT enzyme changes shape in a way that allows it to carry out the key rate-limiting step in PC synthesis. When the amount of PC making up the membrane increases, the CCT falls off the membrane, and PC production ceases.
"The membrane is this big macromolecular array with lots of different molecules in it," Cornell said. "How does this enzyme recognize that 'Oh, I should slow down because the PC content of the membrane is getting too high?'"
Cornell and her project team - a collaboration with Peter Tieleman and graduate student, Mohsen Ramezanpour at the University of Calgary and Jaeyong Lee and Svetla Taneva, research associates at SFU - thought that the answer must have to do with the dynamic changes in shape that the enzyme undergoes when it binds to a membrane.
But these changes are difficult to capture with traditional structural biology methods like x-ray crystallography, which take a static snapshot of molecules. Instead, the team used computational simulations of molecular dynamics, which use information about the forces between every individual atom in a molecule to calculate the trajectories of the enzyme's moving parts.
"What it looks like (when you visualize the output) is your big molecule dancing in front of your eyes," Cornell said. "We set up the molecular dynamics simulation not once, not twice, but 40 different (times). It took months and months just to do the computational parts and even more months trying to analyze the data afterward. We actually spent a lot of time once we got the data just looking on the screen at these dancing molecules."
The simulated dance of the CCT molecule showed that when the M-domain, the section of the enzyme that typically binds to the membrane, detaches from a membrane, it snags the active site of the enzyme, preventing it from carrying out its reaction. When the snagging segment was removed from the simulation, the team saw a dramatic bending motion in the docking site for the snagging element, and speculated that this bending would create a better enzyme active site for catalyzing the reaction when attached to a membrane. The team confirmed these mechanisms using biochemical laboratory experiments.
Interestingly, previous genetic studies had shown that mutations in the gene encoding CCT are responsible for rare conditions like spondylometaphyseal dysplasia with cone-rod dystrophy, which causes severe impairments in bone growth and vision, but it was unknown how these changes in the enzyme could lead to such dramatic consequences. Cornell hopes that understanding how the enzyme works could help researchers find out.
"If you have just one small change in CCT, then how is that going to make this whole process of synthesizing PC defective?" Cornell asks. "That's what we're studying right now."
The study was funded by the Canadian Institutes for Health Research.
About the Journal of Biological Chemistry
JBC is a weekly peer-reviewed scientific journal that publishes research "motivated by biology, enabled by chemistry" across all areas of biochemistry and molecular biology. The read the latest research in JBC, visit http://www.
About the American Society for Biochemistry and Molecular Biology
The ASBMB is a nonprofit scientific and educational organization with more than 12,000 members worldwide. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, at nonprofit research institutions and in industry. The Society's student members attend undergraduate or graduate institutions. For more information about ASBMB, visit http://www.
Sasha Mushegian | EurekAlert!
Scientists develop method to standardize genetic data analysis
10.11.2019 | Moscow Institute of Physics and Technology
Gene mutations associated with autistic behavior are also responsible for disturbances in the gastrointestinal tract
10.11.2019 | Universitätsklinikum Heidelberg
In two experiments performed at the free-electron laser FLASH in Hamburg a cooperation led by physicists from the Heidelberg Max Planck Institute for Nuclear physics (MPIK) demonstrated strongly-driven nonlinear interaction of ultrashort extreme-ultraviolet (XUV) laser pulses with atoms and ions. The powerful excitation of an electron pair in helium was found to compete with the ultrafast decay, which temporarily may even lead to population inversion. Resonant transitions in doubly charged neon ions were shifted in energy, and observed by XUV-XUV pump-probe transient absorption spectroscopy.
An international team led by physicists from the MPIK reports on new results for efficient two-electron excitations in helium driven by strong and ultrashort...
An international research group has observed new quantum properties on an artificial giant atom and has now published its results in the high-ranking journal Nature Physics. The quantum system under investigation apparently has a memory - a new finding that could be used to build a quantum computer.
The research group, consisting of German, Swedish and Indian scientists, has investigated an artificial quantum system and found new properties.
Researchers at the U.S. Department of Energy's (DOE) Argonne National Laboratory have reported a new mechanism to speed up the charging of lithium-ion...
Northwestern University chemists have used visible light and extremely tiny nanoparticles to quickly and simply make molecules that are of the same class as...
Almost everyone uses nanometer-sized alumina these days - this mineral, among others, constitutes the skeleton of modern catalytic converters in cars. Until now, the practical production of nanocorundum with a sufficiently high porosity has not been possible. The situation has changed radically with the presentation of a new method of nanocorundum production, developed as part of a German-Polish cooperation of scientists from Mülheim an der Ruhr and Cracow.
High temperatures and pressures, processes lasting for even dozens of days. Current methods of producing nanometer-sized alumina, a material of significant...
05.11.2019 | Event News
30.10.2019 | Event News
02.10.2019 | Event News
08.11.2019 | Earth Sciences
08.11.2019 | Earth Sciences
08.11.2019 | Trade Fair News