v-SNARE transmembrane domains function as catalysts for vesicle fusion

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Abstract

Vesicle fusion is mediated by assembly of SNARE proteins between opposing membranes, but it is unknown whether transmembrane domains (TMDs) of SNARE proteins serve mechanistic functions that go beyond passive anchoring of the force-generating SNAREpin to the fusing membranes. Here, we show that conformational flexibility of synaptobrevin-2 TMD is essential for efficient Ca2⁺-triggered exocytosis and actively promotes membrane fusion as well as fusion pore expansion. Specifically, introduction of helix-stabilizing leucine residues within the TMD region spanning the vesicle's outer leaflet strongly impairs exocytosis and decelerates fusion pore dilation. In contrast, increasing the number of helix-destabilizing, ß-branched valine or isoleucine residues within the TMD restores normal secretion but accelerates fusion pore expansion beyond the rate found for the wildtype protein. These observations provide evidence that the synaptobrevin-2 TMD catalyzes the fusion process by its structural flexibility, actively setting the pace of fusion pore expansion.

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Madhurima Dhara

Institute for Physiology, Saarland University, Homburg, Germany

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The authors declare that no competing interests exist.
Antonio Yarzagaray

Institute for Physiology, Saarland University, Homburg, Germany

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The authors declare that no competing interests exist.
Mazen Makke

Institute for Physiology, Saarland University, Homburg, Germany

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The authors declare that no competing interests exist.
Barbara Schindeldecker

Institute for Physiology, Saarland University, Homburg, Germany

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The authors declare that no competing interests exist.
Yvonne Schwarz

Institute for Physiology, Saarland University, Homburg, Germany

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The authors declare that no competing interests exist.
Ahmed Shaaban

Zentrum für Human- und Molekularbiologie, Saarland University, Homburg, Germany

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The authors declare that no competing interests exist.
Satyan Sharma

Group Nanoscale Cell Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany

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The authors declare that no competing interests exist.
Rainer A Böckmann

Computational Biology, Friedrich-Alexander University, Erlangen, Germany

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The authors declare that no competing interests exist.
Manfred Lindau

Group Nanoscale Cell Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany

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The authors declare that no competing interests exist.
Ralf Mohrmann

Zentrum für Human- und Molekularbiologie, Saarland University, Homburg, Germany

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The authors declare that no competing interests exist.
Dieter Bruns

Institute for Physiology, Saarland University, Homburg, Germany

For correspondence
dieter.bruns@uks.eu

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The authors declare that no competing interests exist.

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