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Wbox2: A clathrin terminal domain–derived peptide inhibitor of clathrin-mediated endocytosis

Clathrin-mediated endocytosis (CME) occurs via the formation of clathrin-coated vesicles from clathrin-coated pits (CCPs). Clathrin is recruited to CCPs through interactions between the AP2 complex and its N-terminal domain, which in turn recruits endocytic accessory proteins. Inhibitors of CME that...

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Autores principales: Chen, Zhiming, Mino, Rosa E., Mettlen, Marcel, Michaely, Peter, Bhave, Madhura, Reed, Dana Kim, Schmid, Sandra L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480105/
https://www.ncbi.nlm.nih.gov/pubmed/32520988
http://dx.doi.org/10.1083/jcb.201908189
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author Chen, Zhiming
Mino, Rosa E.
Mettlen, Marcel
Michaely, Peter
Bhave, Madhura
Reed, Dana Kim
Schmid, Sandra L.
author_facet Chen, Zhiming
Mino, Rosa E.
Mettlen, Marcel
Michaely, Peter
Bhave, Madhura
Reed, Dana Kim
Schmid, Sandra L.
author_sort Chen, Zhiming
collection PubMed
description Clathrin-mediated endocytosis (CME) occurs via the formation of clathrin-coated vesicles from clathrin-coated pits (CCPs). Clathrin is recruited to CCPs through interactions between the AP2 complex and its N-terminal domain, which in turn recruits endocytic accessory proteins. Inhibitors of CME that interfere with clathrin function have been described, but their specificity and mechanisms of action are unclear. Here we show that overexpression of the N-terminal domain with (TDD) or without (TD) the distal leg inhibits CME and CCP dynamics by perturbing clathrin interactions with AP2 and SNX9. TDD overexpression does not affect clathrin-independent endocytosis or, surprisingly, AP1-dependent lysosomal trafficking from the Golgi. We designed small membrane–permeant peptides that encode key functional residues within the four known binding sites on the TD. One peptide, Wbox2, encoding residues along the W-box motif binding surface, binds to SNX9 and AP2 and potently and acutely inhibits CME.
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spelling pubmed-74801052020-09-21 Wbox2: A clathrin terminal domain–derived peptide inhibitor of clathrin-mediated endocytosis Chen, Zhiming Mino, Rosa E. Mettlen, Marcel Michaely, Peter Bhave, Madhura Reed, Dana Kim Schmid, Sandra L. J Cell Biol Article Clathrin-mediated endocytosis (CME) occurs via the formation of clathrin-coated vesicles from clathrin-coated pits (CCPs). Clathrin is recruited to CCPs through interactions between the AP2 complex and its N-terminal domain, which in turn recruits endocytic accessory proteins. Inhibitors of CME that interfere with clathrin function have been described, but their specificity and mechanisms of action are unclear. Here we show that overexpression of the N-terminal domain with (TDD) or without (TD) the distal leg inhibits CME and CCP dynamics by perturbing clathrin interactions with AP2 and SNX9. TDD overexpression does not affect clathrin-independent endocytosis or, surprisingly, AP1-dependent lysosomal trafficking from the Golgi. We designed small membrane–permeant peptides that encode key functional residues within the four known binding sites on the TD. One peptide, Wbox2, encoding residues along the W-box motif binding surface, binds to SNX9 and AP2 and potently and acutely inhibits CME. Rockefeller University Press 2020-06-10 /pmc/articles/PMC7480105/ /pubmed/32520988 http://dx.doi.org/10.1083/jcb.201908189 Text en © 2020 Chen et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Zhiming
Mino, Rosa E.
Mettlen, Marcel
Michaely, Peter
Bhave, Madhura
Reed, Dana Kim
Schmid, Sandra L.
Wbox2: A clathrin terminal domain–derived peptide inhibitor of clathrin-mediated endocytosis
title Wbox2: A clathrin terminal domain–derived peptide inhibitor of clathrin-mediated endocytosis
title_full Wbox2: A clathrin terminal domain–derived peptide inhibitor of clathrin-mediated endocytosis
title_fullStr Wbox2: A clathrin terminal domain–derived peptide inhibitor of clathrin-mediated endocytosis
title_full_unstemmed Wbox2: A clathrin terminal domain–derived peptide inhibitor of clathrin-mediated endocytosis
title_short Wbox2: A clathrin terminal domain–derived peptide inhibitor of clathrin-mediated endocytosis
title_sort wbox2: a clathrin terminal domain–derived peptide inhibitor of clathrin-mediated endocytosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480105/
https://www.ncbi.nlm.nih.gov/pubmed/32520988
http://dx.doi.org/10.1083/jcb.201908189
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