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Crystal structure of afadin PDZ domain-nectin-3 complex shows the structural plasticity of the ligand-binding site.


ABSTRACT: 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-?-X-? (?, 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 ? sheet between ?2 strands. A major structural change compared with the known AFPDZ structures was observed in the ?2 helix. We found an approximately 2.5 Å-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.

SUBMITTER: Fujiwara Y 

PROVIDER: S-EPMC4353363 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Crystal structure of afadin PDZ domain-nectin-3 complex shows the structural plasticity of the ligand-binding site.

Fujiwara Yoshie Y   Goda Natsuko N   Tamashiro Tomonari T   Narita Hirotaka H   Satomura Kaori K   Tenno Takeshi T   Nakagawa Atsushi A   Oda Masayuki M   Suzuki Mamoru M   Sakisaka Toshiaki T   Takai Yoshimi Y   Hiroaki Hidekazu H  

Protein science : a publication of the Protein Society 20150113 3


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 contai  ...[more]

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