Structural basis for NHERF recognition by ERM proteins.
The Na+/H+ exchanger regulatory factor (NHERF) is a key adaptor protein involved in the anchoring of ion channels and receptors to the actin cytoskeleton through binding to ERM (ezrin/radixin/moesin) proteins. NHERF binds the FERM domain of ERM proteins, although NHERF has no signature Motif-1 sequence for FERM binding found in adhesion molecules. The crystal structures of the radixin FERM domain complexed with the NHERF-1 and NHERF-2 C-terminal peptides revealed a peptide binding site of the FERM domain specific for the 13 residue motif MDWxxxxx(L/I)Fxx(L/F) (Motif-2), which is distinct from Motif-1. This Motif-2 forms an amphipathic alpha helix for hydrophobic docking to subdomain C of the FERM domain. This docking causes induced-fit conformational changes in subdomain C and affects binding to adhesion molecule peptides, while the two binding sites are not overlapped. Our studies provide structural paradigms for versatile ERM linkages between membrane proteins and the cytoskeleton.
Terawaki
Shin-ichi
S
Structural Biology Laboratory, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
Maesaki
Ryoko
R
Hakoshima
Toshio
T
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000737:chemistry; D003599:Cytoskeleton / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D017923:Sodium-Hydrogen Exchangers; D055672:Static Electricity; D013997:Time Factors; D014157:Transcription Factors / Q000737:chemistry*
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; C513242:Etv5 protein, mouse; C480027:ICAM-2 protein, mouse; D010455:Peptides; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; D014157:Transcription Factors; C093376:sodium-hydrogen exchanger regulatory factor