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Publication Abstract from PubMed

Afadin, a scaffold protein localized in adherens junctions (AJs), links nectins to the actin cytoskeleton. Nectins are the major cell adhesion molecules of AJs. At the initial stage of cell-cell junction formation, the nectin-afadin interaction plays an indispensable role in AJ biogenesis via recruiting and tethering other components. The afadin PDZ domain (AFPDZ) is responsible for binding the cytoplasmic C-terminus of nectins. AFPDZ is a class II PDZ domain member, which prefers ligands containing a class II PDZ-binding motif, X-Phi-X-Phi (Phi, hydrophobic residues); both nectins and other physiological AFPDZ targets contain this class II motif. Here, we report the first crystal structure of the AFPDZ in complex with the nectin-3 C-terminal peptide containing the class II motif. We engineered the nectin-3 C-terminal peptide and AFPDZ to produce an AFPDZ-nectin-3 fusion protein and succeeded in obtaining crystals of this complex as a dimer. This novel dimer interface was created by forming an antiparallel beta sheet between beta2 strands. A major structural change compared with the known AFPDZ structures was observed in the alpha2 helix. We found an approximately 2.5 A-wider ligand-binding groove, which allows the PDZ to accept bulky class II ligands. Apparently, the last three amino acids of the nectin-3 C-terminus were sufficient to bind AFPDZ, in which the two hydrophobic residues are important.

Crystal structure of afadin PDZ domain-nectin-3 complex shows the structural plasticity of the ligand-binding site.,Fujiwara Y, Goda N, Tamashiro T, Narita H, Satomura K, Tenno T, Nakagawa A, Oda M, Suzuki M, Sakisaka T, Takai Y, Hiroaki H Protein Sci. 2015 Mar;24(3):376-85. doi: 10.1002/pro.2628. Epub 2015 Jan 13. PMID:25534554^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.