A team led by researchers at the Max Delbrück Center has uncovered the main activation mechanism of GBP1, a protein that plays a pivotal role in combating certain bacteria. Their study demonstrates how the protein adopts a special conformation that enables it to encapsulate the invaders, thereby neutralizing them.
Their findings are published in The EMBO Journal in the article titled, “Structural insights into the activation mechanism of antimicrobial GBP1.”
“The dynamin-related human guanylate-binding protein 1 (GBP1) mediates host defenses against microbial pathogens,” wrote the researchers. “Upon GTP binding and hydrolysis, auto-inhibited GBP1 monomers dimerize and assemble into soluble and membrane-bound oligomers, which are crucial for innate immune responses. How higher-order GBP1 oligomers are built from dimers, and how assembly is coordinated with nucleotide-dependent conformational changes, has remained elusive. Here, we present cryo-electron microscopy-based structural data of soluble and membrane-bound GBP1 oligomers, which show that GBP1 assembles in an outstretched dimeric conformation.”
GBP1 is produced by the body’s cells in response to an infection. It binds specifically to GTP, a nucleotide and chemical energy carrier within cells, where it facilitates the defense against bacterial pathogens. Scientists had already known about this defense strategy, but the details of how it worked were not fully understood.
The team used a high-resolution cryo-electron microscope, which allowed them to visualize the protein’s three-dimensional structure, to investigate each step of this mechanism. “GBP1 is initially present as a single building block. When it is activated, it folds out like a Swiss army knife,” explained the paper’s first author, Marius Weismehl, a doctoral student in Oliver Daumke’s lab.
“Thousands of these unfolded proteins then assemble into discs, which in turn stack into tubular structures,” continued Weismehl. “These tubes finally attach to the bacterial membrane, where they reform and wrap around it like a coat.” In this way, GBP1 proteins neutralize the invaders. Uncovering the details of how these large protein structures are built was the main aim of the study. “Our microscopy data impressively show how GBP1 proteins stick to the membrane surfaces like pins and join together via their heads,” said Misha Kudryashev, professor and group leader at the Max Delbrück Center.
“We have identified a molecular level that plays a critical role in the first step of activation,” added Weismehl.
Their results uncovered for the first time the activation mechanism of GBP1, which results in the encapsulation of pathogens with an antimicrobial protein coat.
The team hopes that this fundamental knowledge of the human immune system will help researchers better understand bacterial infectious diseases.