期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 36, 页码 25327-25340出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.548743
关键词
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资金
- National Institutes of Health [P01 DA 12408]
- Danish Medical Research Council
- University of Copenhagen BioScaRT Program of Excellence
- Lundbeck Foundation Center for Biomembranes in Nanomedicine
- Novo Nordisk Foundation
- Fabrikant Vilhelm Pedersen og Hustrus Mindelegat
- Novo Nordisk Fonden [NNF12OC0002181] Funding Source: researchfish
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 C alpha, 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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