title: Structural Basis for Selective Interaction between the ESCRT Regulator HD-PTP and UBAP1.
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.
authors.affiliation: School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Deepankar
authors.initials: D
authors.lastname: Gahloth
authors.affiliation: School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Levy
authors.affiliation: School of Chemistry and Photon Science Institute, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Heaven
authors.affiliation: School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Flavia
authors.initials: F
authors.lastname: Stefani
authors.affiliation: School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Lydia
authors.initials: L
authors.lastname: Wunderley
authors.affiliation: School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Mould
authors.affiliation: School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cliff
authors.affiliation: School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bella
authors.affiliation: School of Chemistry and Photon Science Institute, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Fielding
authors.affiliation: School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK. Electronic address: philip.woodman@manchester.ac.uk.
authors.forename: Philip
authors.initials: P
authors.lastname: Woodman
authors.affiliation: School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK. Electronic address: lydia.tabernero@manchester.ac.uk.
authors.forename: Lydia
authors.initials: L
authors.lastname: Tabernero
mesh_terms: D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C469867:UBAP1 protein, human; C114102:PTPN23 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor
keywords: coiled-coil structure; endosomal ESCRTs regulation; mitogenic signaling downregulation; tumor suppressor phosphatase; ubiquitin-dependent trafficking