Redox-Regulated Lipid Membrane Binding of the PICK1 PDZ Domain

摘要

PICK1 is a PDZ/BAR domain-containing scaffold protein that regulates the trafficking of manynreceptors and ion channels, including AMPA receptors. In addition to binding to a wide spectrum of targetnproteins to be transported, the PICK1 PDZ domain, via its conserved CPCmotif, has also been shown to bindnto lipid membranes. However, the molecular basis of the CPC motif-mediated lipid membrane binding of thenPICK1 PDZ domain is not known. Here we show that the Cys residues in the CPC motif of the PICK1 PDZndomain forms reversible, intermolecular disulfide bonds under mild oxidation conditions. Importantly,nformation of the disulfide-mediated dimer abolishes the lipid membrane binding capacity of the PICK1 PDZndomain and thereby is expected to alter the cellular functions of PICK1. The structures of the PDZ dimersnprovide atomic-scale pictures of disulfide-mediated PICK1 dimer formation and a molecular explanation ofnthe oxidation-induced dissociation of PICK1 from membranes. We propose that the PICK1-mediatedntrafficking processes might be regulated by cellular redox fluctuations under both physiological andnpathophysiological conditions.