Structural basis of eukaryotic cell-cell fusion

Jimena Pérez-Vargas; Thomas Krey; Clari Valansi; Ori Avinoam; Ahmed Haouz; Marc Jamin; Hadas Raveh-Barak; Benjamin Podbilewicz; Félix A. Rey

doi:10.1016/j.cell.2014.02.020

Structural basis of eukaryotic cell-cell fusion

Jimena Pérez-Vargas, Thomas Krey, Clari Valansi, Ori Avinoam, Ahmed Haouz, Marc Jamin, Hadas Raveh-Barak, Benjamin Podbilewicz^*, Félix A. Rey

^*Corresponding author for this work

Institute of Biochemistry

117 Citations (Scopus)

Abstract

Cell-cell fusion proteins are essential in development. Here we show that the C. elegans cell-cell fusion protein EFF-1 is structurally homologous to viral class II fusion proteins. The 2.6 Å crystal structure of the EFF-1 trimer displays the same 3D fold and quaternary conformation of postfusion class II viral fusion proteins, although it lacks a nonpolar "fusion loop," indicating that it does not insert into the target membrane. EFF-1 was previously shown to be required in both cells for fusion, and we show that blocking EFF-1 trimerization blocks the fusion reaction. Together, these data suggest that whereas membrane fusion driven by viral proteins entails leveraging of a nonpolar loop, EFF-1-driven fusion of cells entails trans-trimerization such that transmembrane segments anchored in the two opposing membranes are brought into contact at the tip of the EFF-1 trimer to then, analogous to SNARE-mediated vesicle fusion, zip the two membranes into one.

Original language	English
Journal	Cell
Volume	157
Issue number	2
Pages (from-to)	407-419
Number of pages	13
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2014.02.020
Publication status	Published - 10.04.2014

Funding

F.A.R. was funded by the French “Agence Nationale pour la Recherche” grant ANR-2010-BLAN-1211 01 and by Institut Pasteur, CNRS, and Merck-Serono. B.P. was funded by the ERC Advanced grant 268843 and the Israel Science Foundation (ISF grants 1542/07 and 826/08). B.P. was a Grass fellow at Radcliffe Institute for Advanced Study, Harvard University. We thank Patrick England, Bertrand Raynal, and Patrick Weber of the Pasteur Proteopole for technical help; the staff of synchrotron beamlines PX-I at the Swiss Light Source, Proxima-1 at SOLEIL, and ID23-1 at the European Synchrotron Radiation Facility for help during data collection; Clemens Vonrhein and Gerard Bricogne from Global Phasing Ltd. for methodological concepts; Tom Rapoport and his lab for discussions and for hosting B.P. at Harvard Medical School; and Jorge Verdin Ramos from Technion and the members of the Rey and Podbilewicz labs for discussions.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1016/j.cell.2014.02.020

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title = "Structural basis of eukaryotic cell-cell fusion",

abstract = "Cell-cell fusion proteins are essential in development. Here we show that the C. elegans cell-cell fusion protein EFF-1 is structurally homologous to viral class II fusion proteins. The 2.6 {\AA} crystal structure of the EFF-1 trimer displays the same 3D fold and quaternary conformation of postfusion class II viral fusion proteins, although it lacks a nonpolar {"}fusion loop,{"} indicating that it does not insert into the target membrane. EFF-1 was previously shown to be required in both cells for fusion, and we show that blocking EFF-1 trimerization blocks the fusion reaction. Together, these data suggest that whereas membrane fusion driven by viral proteins entails leveraging of a nonpolar loop, EFF-1-driven fusion of cells entails trans-trimerization such that transmembrane segments anchored in the two opposing membranes are brought into contact at the tip of the EFF-1 trimer to then, analogous to SNARE-mediated vesicle fusion, zip the two membranes into one.",

author = "Jimena P{\'e}rez-Vargas and Thomas Krey and Clari Valansi and Ori Avinoam and Ahmed Haouz and Marc Jamin and Hadas Raveh-Barak and Benjamin Podbilewicz and Rey, \{F{\'e}lix A.\}",

note = "Funding Information: F.A.R. was funded by the French “Agence Nationale pour la Recherche” grant ANR-2010-BLAN-1211 01 and by Institut Pasteur, CNRS, and Merck-Serono. B.P. was funded by the ERC Advanced grant 268843 and the Israel Science Foundation (ISF grants 1542/07 and 826/08). B.P. was a Grass fellow at Radcliffe Institute for Advanced Study, Harvard University. We thank Patrick England, Bertrand Raynal, and Patrick Weber of the Pasteur Proteopole for technical help; the staff of synchrotron beamlines PX-I at the Swiss Light Source, Proxima-1 at SOLEIL, and ID23-1 at the European Synchrotron Radiation Facility for help during data collection; Clemens Vonrhein and Gerard Bricogne from Global Phasing Ltd. for methodological concepts; Tom Rapoport and his lab for discussions and for hosting B.P. at Harvard Medical School; and Jorge Verdin Ramos from Technion and the members of the Rey and Podbilewicz labs for discussions. ",

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AU - Pérez-Vargas, Jimena

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AU - Jamin, Marc

AU - Raveh-Barak, Hadas

AU - Podbilewicz, Benjamin

AU - Rey, Félix A.

N1 - Funding Information: F.A.R. was funded by the French “Agence Nationale pour la Recherche” grant ANR-2010-BLAN-1211 01 and by Institut Pasteur, CNRS, and Merck-Serono. B.P. was funded by the ERC Advanced grant 268843 and the Israel Science Foundation (ISF grants 1542/07 and 826/08). B.P. was a Grass fellow at Radcliffe Institute for Advanced Study, Harvard University. We thank Patrick England, Bertrand Raynal, and Patrick Weber of the Pasteur Proteopole for technical help; the staff of synchrotron beamlines PX-I at the Swiss Light Source, Proxima-1 at SOLEIL, and ID23-1 at the European Synchrotron Radiation Facility for help during data collection; Clemens Vonrhein and Gerard Bricogne from Global Phasing Ltd. for methodological concepts; Tom Rapoport and his lab for discussions and for hosting B.P. at Harvard Medical School; and Jorge Verdin Ramos from Technion and the members of the Rey and Podbilewicz labs for discussions.

PY - 2014/4/10

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N2 - Cell-cell fusion proteins are essential in development. Here we show that the C. elegans cell-cell fusion protein EFF-1 is structurally homologous to viral class II fusion proteins. The 2.6 Å crystal structure of the EFF-1 trimer displays the same 3D fold and quaternary conformation of postfusion class II viral fusion proteins, although it lacks a nonpolar "fusion loop," indicating that it does not insert into the target membrane. EFF-1 was previously shown to be required in both cells for fusion, and we show that blocking EFF-1 trimerization blocks the fusion reaction. Together, these data suggest that whereas membrane fusion driven by viral proteins entails leveraging of a nonpolar loop, EFF-1-driven fusion of cells entails trans-trimerization such that transmembrane segments anchored in the two opposing membranes are brought into contact at the tip of the EFF-1 trimer to then, analogous to SNARE-mediated vesicle fusion, zip the two membranes into one.

AB - Cell-cell fusion proteins are essential in development. Here we show that the C. elegans cell-cell fusion protein EFF-1 is structurally homologous to viral class II fusion proteins. The 2.6 Å crystal structure of the EFF-1 trimer displays the same 3D fold and quaternary conformation of postfusion class II viral fusion proteins, although it lacks a nonpolar "fusion loop," indicating that it does not insert into the target membrane. EFF-1 was previously shown to be required in both cells for fusion, and we show that blocking EFF-1 trimerization blocks the fusion reaction. Together, these data suggest that whereas membrane fusion driven by viral proteins entails leveraging of a nonpolar loop, EFF-1-driven fusion of cells entails trans-trimerization such that transmembrane segments anchored in the two opposing membranes are brought into contact at the tip of the EFF-1 trimer to then, analogous to SNARE-mediated vesicle fusion, zip the two membranes into one.

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JO - Cell

JF - Cell

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ER -

Structural basis of eukaryotic cell-cell fusion

Abstract

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