Stochastic activation and bistability in a Rab GTPase regulatory network

article Stochastic activation and bistability in a Rab GTPase regulatory network published yes Urban Bezeljak author 2A58201A-F248-11E8-B48F-1D18A9856A870000-0003-1365-5631 Hrushikesh Loya author Beata M Kaczmarek author 36FA4AFA-F248-11E8-B48F-1D18A9856A87 Timothy E. Saunders author Martin Loose author 462D4284-F248-11E8-B48F-1D18A9856A870000-0001-7309-9724 MaLo department CaBe department Reconstitution of cell polarity and axis determination in a cell-free system project The eukaryotic endomembrane system is controlled by small GTPases of the Rab family, which are activated at defined times and locations in a switch-like manner. While this switch is well understood for an individual protein, how regulatory networks produce intracellular activity patterns is currently not known. Here, we combine in vitro reconstitution experiments with computational modeling to study a minimal Rab5 activation network. We find that the molecular interactions in this system give rise to a positive feedback and bistable collective switching of Rab5. Furthermore, we find that switching near the critical point is intrinsically stochastic and provide evidence that controlling the inactive population of Rab5 on the membrane can shape the network response. Notably, we demonstrate that collective switching can spread on the membrane surface as a traveling wave of Rab5 activation. Together, our findings reveal how biochemical signaling networks control vesicle trafficking pathways and how their nonequilibrium properties define the spatiotemporal organization of the cell. National Academy of Sciences2020 eng Proceedings of the National Academy of Sciences of the United States of America 0027-8424 1091-6490 32161136 00052182180004010.1073/pnas.1921027117 117126504-6549 https://research-explorer.ista.ac.at/record/8341 https://ist.ac.at/en/news/proteins-as-molecular-switches/ Bezeljak, U., Loya, H., Kaczmarek, B. M., Saunders, T. E., & Loose, M. (2020). Stochastic activation and bistability in a Rab GTPase regulatory network. Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences. <a href="https://doi.org/10.1073/pnas.1921027117">https://doi.org/10.1073/pnas.1921027117</a> Bezeljak, Urban, Hrushikesh Loya, Beata M Kaczmarek, Timothy E. Saunders, and Martin Loose. “Stochastic Activation and Bistability in a Rab GTPase Regulatory Network.” Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 2020. <a href="https://doi.org/10.1073/pnas.1921027117">https://doi.org/10.1073/pnas.1921027117</a>. U. Bezeljak, H. Loya, B. M. Kaczmarek, T. E. Saunders, and M. Loose, “Stochastic activation and bistability in a Rab GTPase regulatory network,” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 12. National Academy of Sciences, pp. 6504–6549, 2020. Bezeljak U, Loya H, Kaczmarek BM, Saunders TE, Loose M. Stochastic activation and bistability in a Rab GTPase regulatory network. Proceedings of the National Academy of Sciences of the United States of America. 2020;117(12):6504-6549. doi:<a href="https://doi.org/10.1073/pnas.1921027117">10.1073/pnas.1921027117</a> U. Bezeljak, H. Loya, B.M. Kaczmarek, T.E. Saunders, M. Loose, Proceedings of the National Academy of Sciences of the United States of America 117 (2020) 6504–6549. Bezeljak, Urban, et al. “Stochastic Activation and Bistability in a Rab GTPase Regulatory Network.” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 12, National Academy of Sciences, 2020, pp. 6504–49, doi:<a href="https://doi.org/10.1073/pnas.1921027117">10.1073/pnas.1921027117</a>. Bezeljak U, Loya H, Kaczmarek BM, Saunders TE, Loose M. 2020. Stochastic activation and bistability in a Rab GTPase regulatory network. Proceedings of the National Academy of Sciences of the United States of America. 117(12), 6504–6549. 75802020-03-12T05:32:26Z2026-04-08T07:24:55Z