title: Single nucleotide polymorphism that accompanies a missense mutation (Gln488His) impedes the dimerization of Hsp90.
abstract: A single nucleotide polymorphism (SNP) that causes a missense mutation of highly conserved Gln488 to His of the alpha isoform of the 90-kDa heat shock protein (Hsp90alpha) molecular chaperone is observed in Caucasians. The mutated Hsp90alpha severely reduced the growth of yeast cells. To investigate this molecular mechanism, we examined the domain-domain interactions of human Hsp90alpha by using bacterial 2-hybrid system. Hsp90alpha 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.
authors.affiliation: Department of Oral Molecular Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kobayakawa
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Yamada
authors.forename: Akio
authors.initials: A
authors.lastname: Mizuno
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ohara-Nemoto
authors.forename: Tomomi T
authors.initials: TT
authors.lastname: Baba
authors.forename: Takayuki K
authors.initials: TK
authors.lastname: Nemoto
mesh_terms: D019281:Dimerization; D004926:Escherichia coli / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D054730:Protein Interaction Domains and Motifs
chemical_list: D018841:HSP90 Heat-Shock Proteins