NMR uncovers direct interaction between human NEDD4-1 and p34SEI-1

Biochem Biophys Res Commun. 2017 Aug 26;490(3):984-990. doi: 10.1016/j.bbrc.2017.06.151. Epub 2017 Jun 27.

Abstract

PTEN, an important tumor suppressor and a key regulator of the PI3K/AKT signaling pathway, is often deleted/mutated in different types of cancer. The E3 ubiquitin ligase NEDD4-1 catalyzes the polyubiquitination of PTEN, thereby acting as a negative regulator of PTEN. Stability of NEDD4-1, in turn, is tightly controlled by a 34 kDa oncoprotein, p34SEI-1 and it regulates PTEN degradation and activates PI3K/AKT pathway, resulting in cancer metastasis. p34SEI-1 affects not only the expression of NEDD4-1 during transcription and translation but also the subcellular localization of PTEN. This emphasizes the need to understand, at molecular level, the interaction between NEDD4-1 and p34SEI-1. A recent study showed that NEDD4-1 interacts with p34SEI-1 via its WWI domain. However, a detailed interaction for molecular level is yet unknown. We report that the WW1 domain of NEDD4-1 recognizes the SERTA domain containing the proline rich region (PRR motif) in p34SEI-1. TALOS analysis based on NMR data confirms three conserved β-sheets in NEDD4-1 WW1 and the central β-sheet of NEDD4-1 WW1 plays a role for protein stability by the backbone dynamics experiments. NMR titration data revealed the binding site for p34SEI-1 with NEDD4-1. Our data will provide insights into the molecular mechanism of NEDD4-1 and p34SEI-1 interaction, which will be directly used for drug design which inhibits the molecular interaction involved in different cancer signaling.

Keywords: NEDD4-1; NMR (nuclear magnetic resonance); PTEN; p34(SEI−1).

MeSH terms

  • Amino Acid Sequence
  • Endosomal Sorting Complexes Required for Transport / chemistry
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Humans
  • Models, Molecular
  • Nedd4 Ubiquitin Protein Ligases
  • Nuclear Magnetic Resonance, Biomolecular
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Protein Interaction Domains and Motifs
  • Protein Interaction Maps
  • Sequence Alignment
  • Trans-Activators / chemistry
  • Trans-Activators / metabolism*
  • Transcription Factors
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Endosomal Sorting Complexes Required for Transport
  • Nuclear Proteins
  • SERTAD1 protein, human
  • Trans-Activators
  • Transcription Factors
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, human
  • Ubiquitin-Protein Ligases