NMR uncovers direct interaction between human NEDD4-1 and p34 SEI-1

• Published in: Biochemical and biophysical research communications 2017-08, Vol.490 (3), p.984
• Main Authors: Shrestha, Pravesh, Yun, Ji-Hye, Ko, Yoon-Joo, Yeon, Kyu Jeong, Kim, Dooseop, Lee, Heejong, Jin, Dong-Hoon, Nam, Ki-Yup, Yoo, Hye Dong, Lee, Weontae
• Format: Article
• Language: English
• Subjects: 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; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1090-2104

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, p34 and it regulates PTEN degradation and activates PI3K/AKT pathway, resulting in cancer metastasis. p34 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 p34 . A recent study showed that NEDD4-1 interacts with p34 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 p34 . 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 p34 with NEDD4-1. Our data will provide insights into the molecular mechanism of NEDD4-1 and p34 interaction, which will be directly used for drug design which inhibits the molecular interaction involved in different cancer signaling.