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First published online October 12, 2006
doi: 10.1242/10.1242/jcs.03196

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Scavenging of 14-3-3 proteins reveals their involvement in the cell-surface transport of ATP-sensitive K⁺ channels

Katja Heusser^1,*, Hebao Yuan^1,*, Ioana Neagoe¹, Andrei I. Tarasov², Frances M. Ashcroft² and Blanche Schwappach^1,

¹ Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany
² University Laboratory of Physiology, Parks Road, Oxford, OX1 3PT, UK

Author for correspondence (e-mail: b.schwappach{at}zmbh.uni-heidelberg.de)

Accepted 1 August 2006

Arginine (Arg)-based endoplasmic reticulum (ER)-localization signals are involved in the quality control of different heteromultimeric membrane protein complexes. ATP-sensitive potassium (K_ATP) channels are unique because each subunit in the heterooctamer contains an Arg-based ER-localization signal. We have dissected the inactivation events that override the ER-localization activity of the eight peptide-sorting motifs. Employing a 14-3-3-scavenger construct to lower the availability of 14-3-3 proteins, we found that 14-3-3 proteins promote the cell-surface expression of heterologously expressed and native K_ATP channels. 14-3-3 proteins were detected in physical association with K_ATP channels in a pancreatic ß-cell line. Our results suggest that the Arg-based signal present in Kir6.2 is sterically masked by the SUR1 subunit. By contrast, 14-3-3 proteins functionally antagonized the Arg-based signal present in SUR1. The last ten amino acids were required for efficient 14-3-3 recruitment to multimeric forms of the Kir6.2 C-terminus. Channels containing a pore-forming subunit lacking these residues reached the cell surface inefficiently but were functionally indistinguishable from channels formed by the full-length subunits. In conclusion, 14-3-3 proteins promote the cell-surface transport of correctly assembled complexes but do not regulate the activity of K_ATP channels at the cell surface.

Key words: Membrane protein assembly, Quality control, ER-localization signals, ABC proteins, Inward rectifier potassium channels, 14-3-3 proteins

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