Publication Date:
2015-07-01
Description:
Fusion and fission drive all vesicular transport. Although topologically opposite, these reactions pass through the same hemi-fusion/fission intermediate, characterized by a 'stalk' 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.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 reaction, the force bimodality might constitute a general paradigm for leakage-free membrane remodelling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529379/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529379/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mattila, Juha-Pekka -- Shnyrova, Anna V -- Sundborger, Anna C -- Hortelano, Eva Rodriguez -- Fuhrmans, Marc -- Neumann, Sylvia -- Muller, Marcus -- Hinshaw, Jenny E -- Schmid, Sandra L -- Frolov, Vadim A -- R01 GM042455/GM/NIGMS NIH HHS/ -- R01-GM42455/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2015 Aug 6;524(7563):109-13. doi: 10.1038/nature14509. Epub 2015 Jun 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas 75201, USA. ; Biophysics Unit (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of The Basque Country, 48940 Leioa, Spain. ; Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA. ; Institute for Theoretical Physics, Georg-August University, 37077 Gottingen, Germany. ; Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA. ; 1] Biophysics Unit (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of The Basque Country, 48940 Leioa, Spain [2] IKERBASQUE, Basque Foundation of Science, 48011 Bilbao, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26123023" target="_blank"〉PubMed〈/a〉
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
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Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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