• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • Human ether a go go related gene HERG encodes the


    Human-ether-a-go-go-related gene (HERG) encodes the α-subunit of rapidly-activating delayed-rectifier potassium pitavastatin that generate IKr. This outward potassium current is elicited during the plateau phase of action potentials and is required for repolarization [4]. After being translated in the endoplasmic reticulum (ER), the HERG protein is transported to the Golgi apparatus where it undergoes glycosylation [5]. This modification transforms the protein from the premature form into the mature form. Eventually, HERG is transported to the plasma membrane [6]. LQTS type 2 (LQT2) is caused by mutations in HERG [7]. In most LQT2 cases, the mutations destabilize the HERG protein and impair its maturation and intracellular transport [8]. Sorted by the ER quality control system, the mutant HERG protein is reverse-transported from the ER to the cytoplasm where it is degraded by the ubiquitin–proteasome system, resulting in reduced HERG channel currents and impaired repolarization of ventricular action potentials [9]. It has been reported that heat shock (HS) assists both in the folding of newly synthesized proteins and the refolding of denatured proteins [10]. Molecular chaperones such as heat shock proteins (HSPs), including Hsp90 and Hsp70, induced by HS play an important role in the maturation of HERG [11,12]. In mammals, the heat shock factor (HSF) family consists of 4 subtypes and increases in response to HS to activate the transcription of molecular chaperones.
    Materials and methods
    Discussion The novel HERG mutation A78T, found in a patient with LQT2, was located at the N-terminus of HERG proteins. The A78T-HERG protein failed to mature and was expressed as a highly ubiquitinated 135-kDa immature protein. Since ubiquitination of the protein to be degraded by the proteasome is known to occur in the core-glycosylated immature form at the ER [11,12], this finding indicates the impaired stability of A78T-HERG proteins to be degraded via the ubiquitin proteasome system. Protein maturation is facilitated by the accumulation of immature proteins (mass effect) as well as by posttranslational modifications including glycosylation. In the present study, MG132 increased the expression of the 135-kDa immature form of A78T-HERG, but not that of the 155-kDa mature form, suggesting that the accumulation of immature A78T-HERG did not facilitate its maturation. We previously demonstrated that MG132 increased the expression of the mature form of Kv1.5, a voltage-gated potassium channel, indicating that accumulated immature wild-type Kv1.5 protein could be converted to its mature form as a result of the mass effect [14]. Since a substantial portion of Kv1.5 is degraded via the ubiquitin–proteasome system, proteasomal inhibition results in the accumulation of a large amount of immature Kv1.5, facilitating its maturation as a mass effect. In contrast, during the synthesis of WT-HERG, most of the core-glycosylated immature protein is converted to the fully-glycosylated mature form [6]. Thus, accumulation of the immature form of HERG protein in a setting of proteasomal inhibition is lower than that of Kv1.5. The failure of MG132 to increase the expression of mature A78T-HERG suggests that accumulation of immature A78T-HERG is not sufficient to exert a mass effect, while accumulation of immature A78T-HERG may not increase its mature form because of severe dysfunction of its maturation process. Since the type and position of a mutation in the gene influence protein structure and stability [13], the A78T mutation may destabilize the HERG protein because of an alteration in the molecular radius or hydrophobicity of the amino acid at position 78. A78G-HERG yielded the mature protein, whereas A78V-HERG, similarly to A78T-HERG, did not. The former finding excludes the possibility that deletion of the methyl group by substitution for alanine destabilizes the A78T-HERG protein. The latter finding suggests that the larger molecular radius but not hydrophilicity of the threonine residue destabilizes A78T-HERG.