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

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

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