Researchers uncover mechanism that switches off cell transport regulating proteins

Published on December 20, 2012 at 12:20 AM · No Comments

Using X-ray structure analysis, the researchers first determined the spatial structure of the protein complex. The data showed a finger of the amino acid arginine, and a second finger of glutamine. The arginine finger was already known from Ras. The glutamine finger is new and surprising. RabGAP penetrates into the GTP-binding pocket of Rab with both fingers and accelerates the GTP cleavage over five orders of magnitude. The biophysicists observed this dynamic process in real time using FTIR spectroscopy. "In contrast to X-ray structure analysis, FTIR spectroscopy not only gives us a snapshot of the reaction, but an entire film", says PD Dr. Carsten K-tting. The result: both catalytic fingers penetrate simultaneously into the GTP-binding pocket and leave it with the phosphate cleaved from the GTP.

Medically interesting mechanism

In their experiment, the researchers examined the protein Rab1b and the RabGAP TBC1D20. Other Rab proteins and RabGAPs are similar to these two representatives. "Thus, we assume that they also interact via a two-finger mechanism", Konstantin Gavriljuk speculates. The ability of the two-finger system to also switch off mutated Rab proteins, i.e. mutated GTPases, could also be medically very interesting. It would be conceivable to develop small molecules that mimic the two-finger mechanism, and thus switch off other mutant GTPases, such as Ras, which emit uncontrolled growth signals and thus are involved in tumour formation.

Source: Ruhr-University Bochum

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