A hemi-fission intermediate links two mechanistically distinct stages of membrane fission

Juha Pekka Mattila, Anna V. Shnyrova, Anna C. Sundborger, Eva Rodriguez Hortelano, Marc Fuhrmans, Sylvia Neumann, Marcus Müller, Jenny E. Hinshaw, Sandra L. Schmid, Vadim A. Frolov

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Abstract

Fusion and fission drive all vesicular transport. Although topologically opposite, these reactions pass through the same hemi-fusion/fission intermediate, characterized by a âstalkâ in which only the outer membrane monolayers of the two compartments have merged to form a localized non-bilayer connection. Formation of the hemi-fission intermediate requires energy input from proteins catalysing membrane remodelling; however, the relationship between protein conformational rearrangements and hemi-fusion/fission remains obscure. Here we analysed how the GTPase cycle of human dynamin 1, the prototypical membrane fission catalyst, is directly coupled to membrane remodelling. We used intramolecular chemical crosslinking to stabilize dynamin in its GDP·AlF 4 â ' -bound transition state. In the absence of GTP this conformer produced stable hemi-fission, but failed to progress to complete fission, even in the presence of GTP. Further analysis revealed that the pleckstrin homology domain (PHD) locked in its membrane-inserted state facilitated hemi-fission. A second mode of dynamin activity, fuelled by GTP hydrolysis, couples dynamin disassembly with cooperative diminishing of the PHD wedging, thus destabilizing the hemi-fission intermediate to complete fission. Molecular simulations corroborate the bimodal character of dynamin action and indicate radial and axial forces as dominant, although not independent, drivers of hemi-fission and fission transformations, respectively. Mirrored in the fusion reaction, the force bimodality might constitute a general paradigm for leakage-free membrane remodelling.

Original languageEnglish (US)
Pages (from-to)109-113
Number of pages5
JournalNature
Volume524
Issue number7563
DOIs
StatePublished - Aug 6 2015

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Mattila, J. P., Shnyrova, A. V., Sundborger, A. C., Hortelano, E. R., Fuhrmans, M., Neumann, S., Müller, M., Hinshaw, J. E., Schmid, S. L., & Frolov, V. A. (2015). A hemi-fission intermediate links two mechanistically distinct stages of membrane fission. Nature, 524(7563), 109-113. https://doi.org/10.1038/nature14509