Elevator Tripartite ATP-independent periplasmic (TRAP) transporter shows a monomeric elevator architecture
Elevator Tripartite ATP-independent periplasmic (TRAP) transporters are found among various bacteria and archaea. They are situated in the periplasmic space and act as transport proteins for organic acids and related molecules. Though TRAP transporters are known to harbor two transmembrane domains and one soluble substrate-binding protein domain, until now the exact molecular structure remained elusive. Scientists of the excellence cluster ImmunoSensation2 at the University of Bonn in cooperation with colleagues of the University of York have now identified the structure of the TRAP transporter HiSiaQM. A functional analysis further revealed potential target areas for transporter inhibition. The study has now been published in the journal Nature Communications.
TRAP transporters help pathogens such as Haemophilus influenzae or Vibrio cholerae to evade the immune system. Sialic acid, which is ubiquitous in human tissue, is taken up by the pathogens via TRAP transporters. Subsequently, the organic acid is incorporated into the bacterial cell wall. "There, it serves as a kind of invisibility cloak for the bacteria to hide from our immune system," says Bonn scientist PD Dr Gregor Hagelueken. The pathogens mimic the surface of endogenous cells, where sialic acid frequently occurs in the form of cell surface glycoproteins.
The researchers from Hagelueken's group at the Institute of Structural Biology of the University Hospital Bonn (UKB) used cryo-electron microscopy (cryoEM) to decipher the structure of the transporter. "Our results represent a real breakthrough, since attempts to decipher the structure of a TRAP transporter had already been going on for about 20 years," says post-doctoral researcher Martin Peter from Bonn. He recalls the moment when it became clear that the monumental task had been accomplished: "At that moment, we were the first to ever see a TRAP transporter. It was then immediately clear to us how the protein works. It moves up and down like an elevator in the membrane.”
In collaboration with Prof. Dr. Ulrich Kubitscheck's group at the Clausius Institute for Physical and Theoretical Chemistry at the University of Bonn, the researchers were able to watch the transporter at work in real time. "The TRAP transporter is found in many disease-causing bacteria," says Hagelueken. "Maybe in the future our structure can help develop antibiotics to make sure the elevator gets stuck." The scientists were also able to generate several single variable domains on heavy chain (VHH) antibodies, binding to the periplasmic side of the TRAP transporter with high affinity. Application of the VHHs effectively inhibited the uptake of sialic acid. These insights into the functional mechanisms of TRAP transporter might help designing inhibitors for therapeutical use in the future.
Publication
Martin F. Peter, Jan A. Ruland, Peer Depping, Niels Schneberger, Emmanuele Severi, Jonas Moecking, Karl Gatterdam, Sarah Tindall, Alexandre Durand, Veronika Heinz, Jan Peter Siebrasse, Paul-Albert Koenig, Matthias Geyer, Christine Ziegler, Ulrich Kubitscheck, Gavin H. Thomas & Gregor Hagelueken: Structural and mechanistic analysis of a tripartite ATP-independent periplasmic TRAP transporter; Nature Communications; https://www.nature.com/articles/s41467-022-31907-y
Contact
PD Dr. Gregor Hagelueken
Institute for Structural Biology
University Hospital Bonn
Phone: +49 228 287-51200
Email: hagelueken(at)uni-bonn.de
