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

• Autores: Juha-Pekka Mattila, Anna V. Shnyrova, Anna C. Sundborger, Eva Rodríguez Hortelano, Marc Fuhrmans, Sylvia Neumann, Marcus Müller, Jenny E. Hinshaw, Sandra L. Schmid, Vadim Frolov
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 524, Nº 7563, 2015, págs. 109-113
• Idioma: inglés
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• Resumen

  • Fusion and fission drive all vesicular transport. Although topologically opposite, these reactions pass through the same hemi-fusion/fission intermediate1,2, characterized by a ‘stalk’ in which only the outer membrane monolayers of the two compartments have merged to form a localized non-bilayer connection1-3. 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 catalyst4-6, is directly coupled to membrane remodelling. We used intramolecular chemical crosslinking to stabilize dynamin in its GDP·AlF4--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 reaction7,8, the force bimodality might constitute a general paradigm for leakage-free membrane remodelling.