Structural Basis for Selective Interaction between the ESCRT Regulator HD-PTP and UBAP1

Endosomal sorting complexes required for transport (ESCRTs) are essential for ubiquitin-dependent degradation of mitogenic receptors, a process often compromised in cancer pathologies. Sorting of ubiquinated receptors via ESCRTs is controlled by the tumor suppressor phosphatase HD-PTP. The specific interaction between HD-PTP and the ESCRT-I subunit UBAP1 is critical for degradation of growth factor receptors and integrins. Here, we present the structural characterization by X-ray crystallography and double electron-electron resonance spectroscopy of the coiled-coil domain of HD-PTP and its complex with UBAP1. The coiled-coil domain adopts an unexpected open and rigid conformation that contrasts with the closed and flexible coiled-coil domain of the related ESCRT regulator Alix. The HD-PTP:UBAP1 structure identifies the molecular determinants of the interaction and provides a molecular basis for the specific functional cooperation between HD-PTP and UBAP1. Our findings provide insights into the molecular mechanisms of regulation of ESCRT pathways that could be relevant to anticancer therapies. [Display omitted] •Crystal structure of the coiled-coil domain of HD-PTP phosphatase with UBAP1•The open and rigid architecture of HD-PTP is essential for functional recognition•Conformation and structural determinants define selectivity in Bro1 proteins Gahloth, Levy et al. present crystal structures of the coiled-coil domain of the HD-PTP phosphatase, a regulator of ESCRT-dependent sorting, and its complex with the ESCRT-I subunit UBAP1. The structure reveals an open architecture critical for specific interactions and provides insights into how HD-PTP regulates mitogenic receptor sorting.