Redox-regulated lipid membrane binding of the PICK1 PDZ domain.
PICK1 is a PDZ/BAR domain-containing scaffold protein that regulates the trafficking of many receptors and ion channels, including AMPA receptors. In addition to binding to a wide spectrum of target proteins to be transported, the PICK1 PDZ domain, via its conserved CPC motif, has also been shown to bind to lipid membranes. However, the molecular basis of the CPC motif-mediated lipid membrane binding of the PICK1 PDZ domain is not known. Here we show that the Cys residues in the CPC motif of the PICK1 PDZ domain forms reversible, intermolecular disulfide bonds under mild oxidation conditions. Importantly, formation of the disulfide-mediated dimer abolishes the lipid membrane binding capacity of the PICK1 PDZ domain and thereby is expected to alter the cellular functions of PICK1. The structures of the PDZ dimers provide atomic-scale pictures of disulfide-mediated PICK1 dimer formation and a molecular explanation of the oxidation-induced dissociation of PICK1 from membranes. We propose that the PICK1-mediated trafficking processes might be regulated by cellular redox fluctuations under both physiological and pathophysiological conditions.
Shi
Yawei
Y
Institute of Biotechnology, Shanxi University, Taiyuan, PR China. yaweishi@sxu.edu.cn
Yu
Jiang
J
Jia
Yuan
Y
Pan
Lifeng
L
Shen
Chong
C
Xia
Jun
J
Zhang
Mingjie
M
D020816:Amino Acid Motifs / Q000235:genetics; D001692:Biological Transport / Q000235:genetics; D055592:Biophysical Phenomena; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D022082:Cellular Structures / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000737:chemistry* / Q000235:genetics; D008563:Membrane Lipids / Q000235:genetics / Q000378:metabolism*; D008566:Membranes / Q000378:metabolism; D010084:Oxidation-Reduction; D054731:PDZ Domains / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D008055:Lipids; D008563:Membrane Lipids; D018091:Receptors, AMPA