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  Auto-regulation of Rab5 GEF activity in Rabex5 by allosteric structural changes, catalytic core dynamics and ubiquitin binding.

Lauer, J., Segeletz, S., Cezanne, A., Guaitoli, G., Raimondi, F., Gentzel, M., et al. (2019). Auto-regulation of Rab5 GEF activity in Rabex5 by allosteric structural changes, catalytic core dynamics and ubiquitin binding. eLife, 8: e46302. doi:10.7554/eLife.46302.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-4F92-E Version Permalink: http://hdl.handle.net/21.11116/0000-0005-4F96-A
Genre: Journal Article

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 Creators:
Lauer, J., Author
Segeletz, S., Author
Cezanne, A., Author
Guaitoli, G., Author
Raimondi, F., Author
Gentzel, M., Author
Alva, V., Author
Habeck, M.1, Author              
Kalaidzidis, Y., Author
Ueffing, M., Author
Lupas, A. N., Author
Gloeckner, C. J., Author
Zerial, M., Author
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1Research Group of Statistical Inverse-Problems in Biophysics, MPI for Biophysical Chemistry, Max Planck Society, ou_1113580              

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 Abstract: Intracellular trafficking depends on the function of Rab GTPases, whose activation is regulated by guanine exchange factors (GEFs). The Rab5 GEF, Rabex5, was previously proposed to be auto-inhibited by its C-terminus. Here, we studied full-length Rabex5 and Rabaptin5 proteins as well as domain deletion Rabex5 mutants using hydrogen deuterium exchange mass spectrometry. We generated a structural model of Rabex5, using chemical cross-linking mass spectrometry and integrative modeling techniques. By correlating structural changes with nucleotide exchange activity for each construct, we uncovered new auto-regulatory roles for the ubiquitin binding domains and the Linker connecting those domains to the catalytic core of Rabex5. We further provide evidence that enhanced dynamics in the catalytic core are linked to catalysis. Our results suggest a more complex auto-regulation mechanism than previously thought and imply that ubiquitin binding serves not only to position Rabex5 but to also control its Rab5 GEF activity through allosteric structural alterations.

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Language(s): eng - English
 Dates: 2019-11-13
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.7554/eLife.46302
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Title: eLife
Source Genre: Journal
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Pages: 22 Volume / Issue: 8 Sequence Number: e46302 Start / End Page: - Identifier: -