Membrane localization is critical for activation of the PICK1 BAR domain |
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Authors: | Madsen Kenneth L Eriksen Jacob Milan-Lobo Laura Han Daniel S Niv Masha Y Ammendrup-Johnsen Ina Henriksen Ulla Bhatia Vikram K Stamou Dimitrios Sitte Harald H McMahon Harvey T Weinstein Harel Gether Ulrik |
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Affiliation: | Department of Neuroscience and Pharmacology, Molecular Neuropharmacology Group and Center for Pharmacogenomics, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Center for Molecular Medicine and Pharmacology, Institute of Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria; Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA; Bio-nanotechnology Laboratory, Nanoscience Center, University of Copenhagen, DK-2100 Copenhagen, Denmark; Laboratory of Molecular Biology, MRC, Hills Road, Cambridge CB2 2QH, UK |
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Abstract: | The PSD-95/Discs-large/ZO-1 homology (PDZ) domain protein, protein interacting with C kinase 1 (PICK1) contains a C-terminal Bin/amphiphysin/Rvs (BAR) domain mediating recognition of curved membranes; however, the molecular mechanisms controlling the activity of this domain are poorly understood. In agreement with negative regulation of the BAR domain by the N-terminal PDZ domain, PICK1 distributed evenly in the cytoplasm, whereas truncation of the PDZ domain caused BAR domain-dependent redistribution to clusters colocalizing with markers of recycling endosomal compartments. A similar clustering was observed both upon truncation of a short putative α-helical segment in the linker between the PDZ and the BAR domains and upon coexpression of PICK1 with a transmembrane PDZ ligand, including the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR2 subunit, the GluR2 C-terminus transferred to the single transmembrane protein Tac or the dopamine transporter C-terminus transferred to Tac. In contrast, transfer of the GluR2 C-terminus to cyan fluorescent protein, a cytosolic protein, did not elicit BAR domain-dependent clustering. Instead, localizing PICK1 to the membrane by introducing an N-terminal myristoylation site produced BAR domain-dependent, but ligand-independent, PICK1 clustering. The data support that in the absence of PDZ ligand, the PICK1 BAR domain is inhibited through a PDZ domain-dependent and linker-dependent mechanism. Moreover, they suggest that unmasking of the BAR domain's membrane-binding capacity is not a consequence of ligand binding to the PDZ domain per se but results from, and coincides with, recruitment of PICK1 to a membrane compartment. |
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Keywords: | BAR domains PDZ domains protein–lipid interactions receptors transporters |
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