Substitution of only two residues of human Hsp90α causes impeded dimerization of Hsp90β

Two isoforms of the 90-kDa heat-shock protein (Hsp90), i.e., Hsp90α and Hsp90β, are expressed in the cytosol of mammalian cells. Although Hsp90 predominantly exists as a dimer, the dimer-forming potential of the β isoform of human and mouse Hsp90 is less than that of the α isoform. The 16 amino acid substitutions located in the 561–685 amino acid region of the C-terminal dimerization domain should be responsible for this impeded dimerization of Hsp90β (Nemoto T, Ohara-Nemoto Y, Ota M, Takagi T, Yokoyama K. Eur J Biochem 233: 1–8, 1995). The present study was performed to define the amino acid substitutions that cause the impeded dimerization of Hsp90β. Bacterial two-hybrid analysis revealed that among the 16 amino acids, the conversion from Ala558 of Hsp90β to Thr566 of Hsp90α and that from Met621 of Hsp90β to Ala629 of Hsp90α most efficiently reversed the dimeric interaction, and that the inverse changes from those of Hsp90α to Hsp90β primarily explained the impeded dimerization of Hsp90β We conclude that taken together, the conversion of Thr566 and Ala629 of Hsp90α to Ala558 and Met621 is primarily responsible for impeded dimerization of Hsp90β

Insights into hERG K+ channel structure and function from NMR studies

The unique gating kinetics of hERG K⁺ channels are critical for normal cardiac repolarization, and patients with mutations in hERG have a markedly increased risk of cardiac arrhythmias and sudden cardiac arrest. HERG K⁺ channels are also remarkably promiscuous with respect to drug binding, which has been a very significant problem for the pharmaceutical industry. Here, we review the progress that has been made in understanding the structure and function of hERG K⁺ channels with a particular focus on nuclear magnetic resonance studies of the domains of the hERG K⁺ channel