Tetrameric Assembly of K+ Channels Requires ER-Located Chaperone Proteins

Kai Li; Qiang Jiang; Xue Bai; Yi-Feng Yang; Mei-Yu Ruan; Shi-Qing Cai

doi:10.1016/j.molcel.2016.10.027

Tetrameric Assembly of K⁺ Channels Requires ER-Located Chaperone Proteins

Mol Cell. 2017 Jan 5;65(1):52-65. doi: 10.1016/j.molcel.2016.10.027. Epub 2016 Dec 1.

Authors

Kai Li¹, Qiang Jiang¹, Xue Bai¹, Yi-Feng Yang², Mei-Yu Ruan², Shi-Qing Cai³

Affiliations

¹ Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Shanghai 200031, PRC.
² Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
³ Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: sqcai@ion.ac.cn.

PMID: 27916661
DOI: 10.1016/j.molcel.2016.10.027

Abstract

Tetrameric assembly of channel subunits in the endoplasmic reticulum (ER) is essential for surface expression and function of K⁺ channels, but the molecular mechanism underlying this process remains unclear. In this study, we found through genetic screening that ER-located J-domain-containing chaperone proteins (J-proteins) are critical for the biogenesis and physiological function of ether-a-go-go-related gene (ERG) K⁺ channels in both Caenorhabditis elegans and human cells. Human J-proteins DNAJB12 and DNAJB14 promoted tetrameric assembly of ERG (and Kv4.2) K⁺ channel subunits through a heat shock protein (HSP) 70-independent mechanism, whereas a mutated DNAJB12 that did not undergo oligomerization itself failed to assemble ERG channel subunits into tetramers in vitro and in C. elegans. Overexpressing DNAJB14 significantly rescued the defective function of human ether-a-go-go-related gene (hERG) mutant channels associated with long QT syndrome (LQTS), a condition that predisposes to life-threatening arrhythmia, by stabilizing the mutated proteins. Thus, chaperone proteins are required for subunit stability and assembly of K⁺ channels.

Keywords: C. elegans; J-protein; chaperone protein; hERG; long QT syndrome; potassium channel; protein biogenesis; protein oligomerization; protein trafficking; subunit assembly.

MeSH terms

Animals
Animals, Genetically Modified
Caenorhabditis elegans / genetics
Caenorhabditis elegans / metabolism*
Caenorhabditis elegans Proteins / chemistry
Caenorhabditis elegans Proteins / genetics
Caenorhabditis elegans Proteins / metabolism*
Cell Line, Tumor
ERG1 Potassium Channel / chemistry
ERG1 Potassium Channel / genetics
ERG1 Potassium Channel / metabolism*
Endoplasmic Reticulum / metabolism*
HEK293 Cells
HSP40 Heat-Shock Proteins / chemistry
HSP40 Heat-Shock Proteins / genetics
HSP40 Heat-Shock Proteins / metabolism*
HSP47 Heat-Shock Proteins / chemistry
HSP47 Heat-Shock Proteins / genetics
HSP47 Heat-Shock Proteins / metabolism*
HSP70 Heat-Shock Proteins / metabolism
Humans
Induced Pluripotent Stem Cells / metabolism
Long QT Syndrome / genetics
Long QT Syndrome / metabolism
Membrane Potentials
Molecular Chaperones
Mutation
Myocytes, Cardiac / metabolism
Potassium Channels / chemistry
Potassium Channels / genetics
Potassium Channels / metabolism*
Protein Multimerization
Protein Stability
Protein Structure, Quaternary
RNA Interference
Shal Potassium Channels / genetics
Shal Potassium Channels / metabolism
Time Factors
Transfection

Substances

Caenorhabditis elegans Proteins
DNAJB12 protein, human
DNAJB14 protein, human
ERG1 Potassium Channel
HSP40 Heat-Shock Proteins
HSP47 Heat-Shock Proteins
HSP70 Heat-Shock Proteins
KCNH2 protein, human
Molecular Chaperones
Potassium Channels
Shal Potassium Channels
UNC-103 protein, C elegans
dnj-1 protein, C elegans

Supplementary concepts

Long Qt Syndrome 2