Single Nucleotide Polymorphism that Accompanies a Missense Mutation (Gln488His) Impedes the Dimerization of Hsp90

• Published in: Protein Journal Vol. 28; no. 1; pp. 24 - 28
• Main Authors: Kobayakawa, Takeshi, Yamada, Shin-ichi, Mizuno, Akio, Ohara-Nemoto, Yuko, Baba, Tomomi T., Nemoto, Takayuki K.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 2009; Springer Nature B.V
• Subjects: Amino acids; Animal Anatomy; Biochemistry; Bioorganic Chemistry; Biophysics; Chaperones; Chemistry; Chemistry and Materials Science; Dimerization; Escherichia coli - genetics; Heat shock proteins; Histology; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humans; Missense mutation; Mitochondria; Molecular modelling; Morphology; Mutation; Mutation, Missense; Organic Chemistry; Polymorphism; Polymorphism, Single Nucleotide; Protein Interaction Domains and Motifs; Single-nucleotide polymorphism; Yeasts; Hsp90; Trap1; Missense mutation; SNP; Dimer formation
• ISSN: 1572-3887; 1573-4943; 1875-8355
• DOI: 10.1007/s10930-008-9160-1

A single nucleotide polymorphism (SNP) that causes a missense mutation of highly conserved Gln488 to His of the α isoform of the 90-kDa heat shock protein (Hsp90α) molecular chaperone is observed in Caucasians. The mutated Hsp90α severely reduced the growth of yeast cells. To investigate this molecular mechanism, we examined the domain–domain interactions of human Hsp90α by using bacterial 2-hybrid system. Hsp90α was expressed as a full-length form, N-terminal domain (residues 1–400), or middle (residues 401–617) plus C-terminal (residues 618–732) domains (MC domain/amino acids 401–732). The Gln488His substitution in MC domain did not affect the intra-molecular interaction with N-terminal domain, whereas the dimeric interaction-mediated by the inter-molecular interaction between MC domains was decreased to 32%. Gln488Ala caused a similar change, whereas Gln488Thr, which exceptionally occurs in mitochondrial Hsp90 paralog, fully maintained the dimeric interaction. Therefore, the SNP causing Gln488His mutation could abrogate the Hsp90 function due to reduced dimerization.