Structural basis for selective interaction between the ESCRT regulator HD-PTP and UBAP1

Deepankar Gahloth, Colin Levy, Graham Heaven, Flavia Stefani, Lydia Wunderley, AP Mould, Matthew Cliff, Jordi Bella, Alistair Fielding, Philip Woodman, Lydia Tabernero

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Abstract

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.
Original languageEnglish
Pages (from-to)0
JournalStructure
Volume24
Issue number12
DOIs
Publication statusPublished - 10 Nov 2016

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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