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Autoregulation clamps the synaptic membrane-remodeling machinery and promotes productive actin-dependent endocytosis

Steven J. Del Signore, Charlotte F. Kelley, Emily M. Messelaar, Tania Lemos, Michelle F. Marchan, Biljana Ermanoska, Markus Mund, Marko Kaksonen, View ORCID ProfileAvital A Rodal
doi: https://doi.org/10.1101/2020.03.06.981076
Steven J. Del Signore
aDepartment of Biology, Brandeis University, 415 South St. Waltham MA USA
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Charlotte F. Kelley
aDepartment of Biology, Brandeis University, 415 South St. Waltham MA USA
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Emily M. Messelaar
aDepartment of Biology, Brandeis University, 415 South St. Waltham MA USA
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Tania Lemos
aDepartment of Biology, Brandeis University, 415 South St. Waltham MA USA
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Michelle F. Marchan
aDepartment of Biology, Brandeis University, 415 South St. Waltham MA USA
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Biljana Ermanoska
aDepartment of Biology, Brandeis University, 415 South St. Waltham MA USA
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Markus Mund
bDepartment of Biochemistry and NCCR Chemical Biology, University of Geneva, 30 Quai Ernest-Ansermet, 1211 Geneva, Switzerland
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Marko Kaksonen
bDepartment of Biochemistry and NCCR Chemical Biology, University of Geneva, 30 Quai Ernest-Ansermet, 1211 Geneva, Switzerland
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Avital A Rodal
aDepartment of Biology, Brandeis University, 415 South St. Waltham MA USA
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  • ORCID record for Avital A Rodal
  • For correspondence: arodal@brandeis.edu
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Abstract

Synaptic membrane-remodeling events such as endocytosis require force-generating actin assembly. The endocytic machinery that regulates these actin and membrane dynamics localizes at high concentrations in a micron-scale synaptic membrane domain called the ‘periactive zone’ (PAZ). Paradoxically, endocytic events occur only sparsely in space and time within the PAZ. Here we describe a mechanism whereby autoinhibition clamps the PAZ machinery to limit actin assembly to discrete functional events. We found that collective interactions between the Drosophila PAZ proteins Nwk/FCHSD2, Dap160/Intersectin, and WASp relieve Nwk autoinhibition and promote robust membrane-coupled actin assembly in vitro. Using automated particle tracking to quantify synaptic actin dynamics in vivo, we discovered that Nwk-Dap160 interactions constrain spurious assembly of WASp-dependent actin structures. These interactions also promote synaptic endocytosis, suggesting that autoinhibition both clamps and primes the synaptic endocytic machinery, thereby constraining actin assembly to drive productive membrane remodeling in response to physiological cues.

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Posted March 07, 2020.
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Autoregulation clamps the synaptic membrane-remodeling machinery and promotes productive actin-dependent endocytosis
Steven J. Del Signore, Charlotte F. Kelley, Emily M. Messelaar, Tania Lemos, Michelle F. Marchan, Biljana Ermanoska, Markus Mund, Marko Kaksonen, Avital A Rodal
bioRxiv 2020.03.06.981076; doi: https://doi.org/10.1101/2020.03.06.981076
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Autoregulation clamps the synaptic membrane-remodeling machinery and promotes productive actin-dependent endocytosis
Steven J. Del Signore, Charlotte F. Kelley, Emily M. Messelaar, Tania Lemos, Michelle F. Marchan, Biljana Ermanoska, Markus Mund, Marko Kaksonen, Avital A Rodal
bioRxiv 2020.03.06.981076; doi: https://doi.org/10.1101/2020.03.06.981076

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