Structural Basis for Specific Interaction of TGFβ Signaling Regulators SARA/Endofin with HD-PTP

Structure. 2017 Jul 5;25(7):1011-1024.e4. doi: 10.1016/j.str.2017.05.005. Epub 2017 Jun 8.

Abstract

SARA and endofin are endosomal adaptor proteins that drive Smad phosphorylation by ligand-activated transforming growth factor β/bone morphogenetic protein (TGFβ/BMP) receptors. We show in this study that SARA and endofin also recruit the tumor supressor HD-PTP, a master regulator of endosomal sorting and ESCRT-dependent receptor downregulation. High-affinity interactions occur between the SARA/endofin N termini, and the conserved hydrophobic region in the HD-PTP Bro1 domain that binds CHMP4/ESCRT-III. CHMP4 engagement is a universal feature of Bro1 proteins, but SARA/endofin binding is specific to HD-PTP. Crystallographic structures of HD-PTPBro1 in complex with SARA, endofin, and three CHMP4 isoforms revealed that all ligands bind similarly to the conserved site but, critically, only SARA/endofin interact at a neighboring pocket unique to HD-PTP. The structures, together with mutagenesis and binding analysis, explain the high affinity and specific binding of SARA/endofin, and why they compete so effectively with CHMP4. Our data invoke models for how endocytic regulation of TGFβ/BMP signaling is controlled.

Keywords: ESCRT-III; SARA and endofin; TGFβ signaling; crystallographic structures; endosomal effectors; tumor-supressor phosphatase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Endosomal Sorting Complexes Required for Transport / chemistry
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Molecular Docking Simulation*
  • Protein Binding
  • Protein Tyrosine Phosphatases, Non-Receptor / chemistry*
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism
  • Serine Endopeptidases / chemistry*
  • Serine Endopeptidases / metabolism
  • Transforming Growth Factor beta / metabolism

Substances

  • CHMP4B protein, human
  • Endosomal Sorting Complexes Required for Transport
  • Intracellular Signaling Peptides and Proteins
  • Transforming Growth Factor beta
  • PTPN23 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor
  • ZFYVE16 protein, human
  • Serine Endopeptidases