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.
|Number of pages||7|
|Journal||Biochemical and Biophysical Research Communications|
|Publication status||Published - 2017 Aug 26|
Bibliographical noteFunding Information:
This work was supported by Mid-career Researcher Program (NRF-2017R1A2B2008483 to WL) and the Basic Science Research Program (NRF-518 2016R1A6A3A04010213n to J. H. Yun) through the National Research Foundation of Korea funded by the Ministry of Education. This work was supported by a grant from Brain Korea (BK+) graduate student scholarship.
© 2017 Elsevier Inc.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology