Co-chaperone FKBP38 Promotes HERG Trafficking

Abstract

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 (I Kr ). 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.

RING Finger Protein RNF207, a Novel Regulator of Cardiac Excitation

“…It is currently believed that large complexes consisting of the key chaperones HSC70/HSP70 and HSP90, assisted by cochaperones such as HDJ-1/2 (HSP40), HOP, calnexin, calreticulin, and FKBP38 (36,37,(53)(54)(55), are involved in proper HERG folding, assembly, and ER export as well as in the retention of trafficking-deficient or misfolded HERG in the ER. The RNF207-dependent HERG expression (Fig.…”

Functional evolution of Erg potassium channel gating reveals an ancient origin for I Kr

“…DAO is unique to Drosophila, but it contains a tetratricopeptide repeat (TPR domain), which is a widespread protein interaction motif (18). A TPR-containing protein has also been implicated in HsErg1 trafficking (24). Coexpression of CeErg with DAO in Xenopus oocytes remarkably rescued functional expression of CeErg, despite the absence of a DAO ortholog in nematodes (Fig.…”

A Drosophila behavioral mutant, down and out ( dao ), is defective in an essential regulator of Erg potassium channels

“…TPR motifs are thought to mediate protein-protein interactions, and other TPR-containing proteins have functions in cell-cycle control and protein transport and are used as co-chaperones (19,24). Recent studies show that FKBP38, which contains a TPR motif, associates with hERG channels in a cardiac-derived cell line and in HEK-293 cells (25). hERG trafficking is hampered when FKBP38 levels are reduced by small interfering RNA, and the trafficking of an hERG mutant protein associated with long QT (LQT) syndrome is partially rescued when FKBP38 is overexpressed.…”