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

Structure. 2016 Dec 6;24(12):2115-2126. doi: 10.1016/j.str.2016.10.006. Epub 2016 Nov 10.


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.

Keywords: coiled-coil structure; endosomal ESCRTs regulation; mitogenic signaling downregulation; tumor suppressor phosphatase; ubiquitin-dependent trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Carrier Proteins / chemistry*
  • Carrier Proteins / metabolism*
  • Crystallography, X-Ray
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Humans
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Tyrosine Phosphatases, Non-Receptor / chemistry*
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism*


  • Carrier Proteins
  • Endosomal Sorting Complexes Required for Transport
  • UBAP1 protein, human
  • PTPN23 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor