Structural basis for neutral endopeptidase 24.11 recognition by ERM proteins

Structural Biology Laboratory, Nara Institute of Science and Technology* Structural Biology Laboratory, Nara Institute of Science and Technology, Japan. CREST, JST, Japan**
â—‹Shin-ichi Terawaki* Ken Kitano* Toshio Hakoshima**

ERM (Ezrin/Radixin/Moesin) proteins act as a cytoplasmic cross-linker that mediates formation of membrane-associated cytoskeletons by binding both actin filaments and cytoplasmic parts of membrane proteins. Members of this family possess the conserved N-terminal regions, which contain the FERM (Four point one and ERM) domain consisting of about 300 residues. The FERM domain recognizes the cytoplasmic tails of several adhesion molecules such as CD44, CD43 and ICAMs that are classified to type I membrane proteins. Recently, the FERM domain of ERM proteins has been shown to bind to a type II membrane protein, neutral endopeptidase (NEP), which inactivates G protein coupled receptors (GPCRs) by cleaving neuropeptides such as bombesin and neurotensin through the C-terminal extracellular metallopeptidase domain that belongs to the M13 family of zinc peptidases. The NEP-ERM interaction suppresses the cell adhesion by competing with the interaction between hyaluronane receptor CD44 and ERM proteins, while it is obscure how the FERM domain recognizes the N-terminal cytoplasmic tail of NEP that possesses the opposite peptide polarity to type I membrane protein CD44. Here, we determined the crystal structure of the radixin FERM domain complexed with the N-terminal NEP cytoplasmic peptide at 3.2 Å resolution. In the FERM-NEP complex, the NEP peptide locates at a long shallow groove on PTB (phosphotyrosine binding domain)-like subdomain C. This poster presents structural insight into the type II membrane protein recognition by the FERM domain and the suppression of cell adhesion through the interaction of NEP with the FERM domain.