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Clathrin light chain diversity regulates membrane deformation in vitro and synaptic vesicle formation in vivo

Lisa Redlingshöfer, Faye McLeod, Yu Chen, Marine D. Camus, Jemima J. Burden, Ernest Palomer, Kit Briant, Philip N. Dannhauser, Patricia C. Salinas, Frances M. Brodsky
doi: https://doi.org/10.1101/815183
Lisa Redlingshöfer
1Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK
2Institute of Structural and Molecular Biology, Birkbeck and University College London, Malet Street, London WC1E 7HX, UK
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Faye McLeod
3Research Department of Cell and Developmental Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK
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Yu Chen
1Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK
2Institute of Structural and Molecular Biology, Birkbeck and University College London, Malet Street, London WC1E 7HX, UK
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Marine D. Camus
1Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK
2Institute of Structural and Molecular Biology, Birkbeck and University College London, Malet Street, London WC1E 7HX, UK
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Jemima J. Burden
4Medical Research Council Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
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Ernest Palomer
3Research Department of Cell and Developmental Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK
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Kit Briant
1Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK
2Institute of Structural and Molecular Biology, Birkbeck and University College London, Malet Street, London WC1E 7HX, UK
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Philip N. Dannhauser
1Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK
2Institute of Structural and Molecular Biology, Birkbeck and University College London, Malet Street, London WC1E 7HX, UK
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Patricia C. Salinas
3Research Department of Cell and Developmental Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK
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Frances M. Brodsky
1Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK
2Institute of Structural and Molecular Biology, Birkbeck and University College London, Malet Street, London WC1E 7HX, UK
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  • For correspondence: f.brodsky@ucl.ac.uk
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ABSTRACT

Clathrin light chain (CLC) subunits in vertebrates are encoded by paralogous genes CLTA and CLTB and both gene products are alternatively spliced in neurons. To understand how this CLC diversity influences neuronal clathrin function, we characterised the biophysical properties of clathrin comprising individual CLC variants for correlation with neuronal phenotypes of mice lacking either CLC-encoding gene. CLC splice variants differentially influenced clathrin knee conformation within assemblies, and clathrin with neuronal CLC mixtures was more effective in membrane deformation than clathrin with single neuronal isoforms nCLCa or nCLCb. Correspondingly, electrophysiological recordings revealed that neurons from mice lacking nCLCa or nCLCb were both defective in synaptic vesicle replenishment. Mice with only nCLCb had a reduced synaptic vesicle pool and impaired neurotransmission compared to wild-type mice, while nCLCa-only mice had increased synaptic vesicle numbers, restoring normal neurotransmission. These findings highlight differences between the CLC isoforms and show that isoform mixing influences tissue-specific clathrin activity in neurons, which requires their functional balance.

SIGNIFICANCE STATEMENT This study reveals that diversity of clathrin light chain (CLC) subunits alters clathrin properties and demonstrates that the two neuronal CLC subunits work together for optimal clathrin function in synaptic vesicle formation. Our findings establish a role for CLC diversity in synaptic transmission and illustrate how CLC variability expands the complexity of clathrin to serve tissue-specific functions.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • The title has been changed to make it more understandable to a broad audience by replacing the technically defined term budding efficiency with membrane deformation. The author order has been updated to reflect recent contributions and present addresses added. The text has been edited further for clarity throughout and one new reference supporting our findings was added (37). The axis labels in Figures 3b and 3c were corrected to correspond better to the technical definition of the parameters measured.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 28, 2020.
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Clathrin light chain diversity regulates membrane deformation in vitro and synaptic vesicle formation in vivo
Lisa Redlingshöfer, Faye McLeod, Yu Chen, Marine D. Camus, Jemima J. Burden, Ernest Palomer, Kit Briant, Philip N. Dannhauser, Patricia C. Salinas, Frances M. Brodsky
bioRxiv 815183; doi: https://doi.org/10.1101/815183
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Clathrin light chain diversity regulates membrane deformation in vitro and synaptic vesicle formation in vivo
Lisa Redlingshöfer, Faye McLeod, Yu Chen, Marine D. Camus, Jemima J. Burden, Ernest Palomer, Kit Briant, Philip N. Dannhauser, Patricia C. Salinas, Frances M. Brodsky
bioRxiv 815183; doi: https://doi.org/10.1101/815183

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