Figure 6
HD-PTP is a scaffold for ESCRT binding. Our model of HD-PTP regulation of ESCRT function involves coordinated binding and displacement of different ESCRTs during endosomal trafficking of ubiquitinated cargo. First, upon internalisation of activated EGFR, ubiquitinated cargo traffics to ESCRT-0. In Stage 1, the ESCRT-0 subunit STAM2 associates with HD-PTP by binding both via its GAT domain (pink oval) at the Bro1 domain, and via its SH3 domain (pink circle) at the PRR (to an SH3 consensus peptide, PPRPTAPKP). In Stage 2, STAM2/ESCRT-0 is then released from HD-PTPPRR by the ESCRT-I core subunit TSG101, allowing access of UBAP1 to the CC region and stable binding of ESCRT-I to HD-PTP. UBAP1 binds to the conserved region FYX2 L (yellow) in the CC domain and TSG101 binds to the “PTAP” motif (green) within the SH3 consensus. In Stage 3, binding of ESCRT-III (C4: CHMP4 subunit, purple) to the Bro1 domain of HD-PTP further displaces ESCRT-0, driving the cargo into the MVB pathway. Additional factors, including the presence of deubiquitinating enzymes and ESCRT-III polymerisation, would also drive MVB sorting.
