Co-chaperone FKBP38 Promotes HERG Trafficking

The Long QT Syndrome is a cardiac disorder associated with ventricular arrhythmias that can lead to syncope and sudden death. One prominent form of the Long QT syndrome has been linked to mutations in the HERG gene (KCNH2) that encodes the voltage-dependent delayed rectifier potassium channel (IKr)....

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-08, Vol.282 (32), p.23509-23516
Main Authors: Walker, Valerie E., Atanasiu, Roxana, Lam, Hung, Shrier, Alvin
Format: Article
Language:English
Subjects:
Cell Line
Cell Membrane - metabolism
Cytosol - metabolism
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels - metabolism
HSC70 Heat-Shock Proteins - metabolism
HSP90 Heat-Shock Proteins - metabolism
Humans
Mass Spectrometry
Models, Biological
Molecular Chaperones - metabolism
Mutation
Protein Transport
RNA, Small Interfering - metabolism
Tacrolimus Binding Proteins - metabolism
Transfection
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Summary:The Long QT Syndrome is a cardiac disorder associated with ventricular arrhythmias that can lead to syncope and sudden death. One prominent form of the Long QT syndrome has been linked to mutations in the HERG gene (KCNH2) that encodes the voltage-dependent delayed rectifier potassium channel (IKr). In order to search for HERG-interacting proteins important for HERG maturation and trafficking, we conducted a proteomics screen using myc-tagged HERG transfected into cardiac (HL-1) and non-cardiac (human embryonic kidney 293) cell lines. A partial list of putative HERG-interacting proteins includes several known components of the cytosolic chaperone system, including Hsc70 (70-kDa heat shock cognate protein), Hsp90 (90-kDa heat shock protein), Hdj-2, Hop (Hsp-organizing protein), and Bag-2 (BCL-associated athanogene 2). In addition, two membrane-integrated proteins were identified, calnexin and FKBP38 (38-kDa FK506-binding protein, FKBP8). We show that FKBP38 immunoprecipitates and co-localizes with HERG in our cellular system. Importantly, small interfering RNA knock down of FKBP38 causes a reduction of HERG trafficking, and overexpression of FKBP38 is able to partially rescue the LQT2 trafficking mutant F805C. We propose that FKBP38 is a co-chaperone of HERG and contributes via the Hsc70/Hsp90 chaperone system to the trafficking of wild type and mutant HERG potassium channels.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M701006200