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PDBsum entry 2lui
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Protein binding
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PDB id
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2lui
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References listed in PDB file
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Key reference
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Title
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Protein interacting with c-Kinase 1 (pick1) binding promiscuity relies on unconventional psd-95/discs-Large/zo-1 homology (pdz) binding modes for nonclass ii pdz ligands.
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Authors
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S.Erlendsson,
M.Rathje,
P.O.Heidarsson,
F.M.Poulsen,
K.L.Madsen,
K.Teilum,
U.Gether.
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Ref.
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J Biol Chem, 2014,
289,
25327-25340.
[DOI no: ]
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PubMed id
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Abstract
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PDZ domain proteins control multiple cellular functions by governing assembly of
protein complexes. It remains unknown why individual PDZ domains can bind the
extreme C terminus of very diverse binding partners and maintain selectivity. By
employing NMR spectroscopy, together with molecular modeling, mutational
analysis, and fluorescent polarization binding experiments, we identify here
three structural mechanisms explaining why the PDZ domain of PICK1 selectively
binds >30 receptors, transporters, and kinases. Class II ligands, including
the dopamine transporter, adopt a canonical binding mode with promiscuity
obtained via differential packing in the binding groove. Class I ligands, such
as protein kinase Cα, depend on residues upstream from the canonical binding
sequence that are likely to interact with flexible loop residues of the PDZ
domain. Finally, we obtain evidence that the unconventional ligand ASIC1a has a
dual binding mode involving a canonical insertion and a noncanonical internal
insertion with the two C-terminal residues forming interactions outside the
groove. Together with an evolutionary analysis, the data show how unconventional
binding modes might evolve for a protein recognition domain to expand the
repertoire of functionally important interactions.
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