Role of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition

Abstract

In the graphical abstract for the article above, the word ''interferons'' was inadvertently misspelled as ''interterons.'' The graphical abstract has been corrected and is now available online.

Clathrin Terminal Domain-Ligand Interactions Regulate Sorting of Mannose 6-Phosphate Receptors Mediated by AP-1 and GGA Adaptors

“…Application of Pitstop-2 potently inhibited MHCI endocytosis (Fig. 1, D and F) with an IC 50 of ϳ10 -15 M, similar to that reported for CME of transferrin (31). Two control compounds (Pitnot-2 and Pitnot-2-100) structurally related to Pitstop-2 (Fig.…”

“…1, A and B, and Ref. 31). Application of Pitstop-2-100 also potently inhibited MHCI endocytosis (Fig.…”

“…Recently, we identified Pitstop -1 and Pitstop -2 as small molecule inhibitors of clathrin function in CME (31). CME inhibition is based on the ability of Pitstop compounds to interfere with the function of the clathrin TD, a seven-bladed ␤-propeller, as a recruitment hub for accessory proteins harboring clathrin box motifs (31) including AP and GGA adaptors, Eps15, epsins, amphiphysin, SNXs, or CALM (1,3,5,11,32,33).…”

“…CME inhibition is based on the ability of Pitstop compounds to interfere with the function of the clathrin TD, a seven-bladed ␤-propeller, as a recruitment hub for accessory proteins harboring clathrin box motifs (31) including AP and GGA adaptors, Eps15, epsins, amphiphysin, SNXs, or CALM (1,3,5,11,32,33). Although Pitstop-2 has been shown to inhibit CME of transferrin and HIV uptake via arrest of CCP dynamics (31), its activity with respect to intracellular membrane traffic has not been explored.…”

Stabilization of protein–protein interactions by small molecules

“…Of these, two of the most prominent examples are the nutlins developed by Roche [4,5], which inhibit the negative regulation of the tumor suppressor p53 by the ubiquitin ligase mouse double minute 2 homolog (MDM2), and navitoclax from Abbott (ABT263), which disrupts the interaction of the antiapoptotic protein Bcl-2 and apoptosis-executing proteins like Bad, Bid and Bak [6][7][8]. Further prominent examples are molecules that inhibit the interaction of human leukemia-derived growth factor (LDGF) with HIV integrase [9], disrupt the binding of KRas and phosphodiesterase (PDE)d [10], transform an active tumor necrosis factor (TNF)a trimer into an inactive dimer [11] or inhibit the binding of PPI modules like the clathrin terminal domain (CTD), or bromodomains with their partners [12,13].…”