NHERF1/EBP50 head-to-tail intramolecular interaction masks association with PDZ domain ligands.
Loss of cell polarity is one of the initial alterations in the development of human epithelial cancers. Na(+)/H(+) exchanger regulatory factor (NHERF) homologous adaptors 1 and 2 are membrane-associated proteins composed of two amino (N)-terminal PDZ domains and an ezrin-radixin-moesin (ERM)-binding (EB) carboxyl (C)-terminal region. We describe here an intramolecular conformation of NHERF1/EBP50 (ERM-binding phosphoprotein 50) in which the C-terminal EB region binds to the PDZ2 domain. This novel head-to-tail conformation masked the interaction of both PDZ domains with PDZ domain-specific ligands, such as PTEN and beta-catenin. An EB region composite structure comprising an alpha-helix ending in a PDZ-binding motif imparted opposite effects to NHERF1 associations, mediating binding to ERM proteins and inhibiting binding of PDZ domain ligands. The PDZ domain inhibition was released by prior association of ezrin with the EB region, a condition that occurs in vivo and likely disrupts NHERF1 head-to-tail interaction. In contrast, NHERF2 did not present a regulatory mechanism for protein complex formation. Functionally, NHERF1 is required to organize complexes at the apical membranes of polarized epithelial cells. The regulation of NHERF1 interactions at the apical membrane thus appears to be a dynamic process that is important for maintaining epithelial-tissue integrity.
Morales
Fabiana C
FC
Department of Neuro-Oncology, M. D. Anderson Cancer Center, The University of Texas, 6767 Bertner Avenue, Houston, TX 77030, USA.
Takahashi
Yoko
Y
Momin
Safan
S
Adams
Henry
H
Chen
Xiaomin
X
Georgescu
Maria-Magdalena
MM
D002460:Cell Line; D016764:Cell Polarity; D019281:Dimerization; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D008024:Ligands; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; D051176:beta Catenin; C093376:sodium-hydrogen exchanger regulatory factor; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human