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

Zhiming Chen, Rosa E. Mino, Marcel Mettlen, Peter Michaely, Madhura Bhave, Dana Kim Reed, Sandra L. Schmid

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish
Article numbere201908189
JournalJournal of Cell Biology
Issue number9
StatePublished - 7 Sep 2020
Externally publishedYes


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