Fig. 3. Putative modulatory mechanisms of ubiquitylated cargo recognition by endocytic adaptors harboring UIM domains. (A) Ubiquitylation of both cargo and relevant UIM-containing endocytic adaptors (e.g. eps15/eps15R and epsin) may influence the internalization efficiency. (B) Adaptor autoactivation and formation of a signal relay network by adaptor ubiquitylation. Ubiquitin allosterically activates the UIMs. In addition, increased local concentration may facilitate the assembly of a polyvalent adaptor network at the cell surface through intermolecular ubiquitin-UIM interactions, manifesting in higher avidity for oligoubiquitylated cargo. (C) Adaptor autoinhibition by ubiquitylation. Monoubiquitylation-induced intramolecular interaction between ubiquitin and UIM attenuates adaptor affinity for ubiquitylated cargo. (D) Substrate-induced stabilization of heterooligomeric ubiquitin-binding adaptors. Peptide interactions may facilitate the association of ubiquitin-adaptors and synchronous presentation of multiple UIMs, increasing the avidity towards oligoubiquitylated substrate.