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

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Abstract

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.

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Abbreviations

SNP:

Single nucleotide polymorphism

Hsp:

Heat shock protein

Hsp90:

90-kDa Heat shock protein

hHsp90α and hHsp90β:

α and β Isoforms, respectively, of human Hsp90

Grp94:

94-kDa Glucose-regulated protein/endoplasmic reticulum paralog of Hsp90

Trap1:

Mitochondrial paralog of Hsp90

yeast Hsp82 and Hsc82:

82-kDa Heat shock protein and heat shock cognate protein of yeast, respectively

HtpG:

Bacterial ortholog of eukaryotic Hsp90

PAGE:

Polyacrylamide gel electrophoresis

SDS:

Sodium dodecyl sulfate

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Acknowledgments

This work was supported in part by Grants-in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to S.Y.) and from Nagasaki University (Y.O.-N.).

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Authors and Affiliations

  1. Department of Oral Molecular Biology, Course of Medical and Dental Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan

    Takeshi Kobayakawa, Yuko Ohara-Nemoto, Tomomi T. Baba & Takayuki K. Nemoto

  2. Department of Oral and Maxillofacial Surgery, Course of Medical and Dental Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Shin-ichi Yamada & Akio Mizuno

Authors
  1. Takeshi Kobayakawa
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  2. Shin-ichi Yamada
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  3. Akio Mizuno
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  4. Yuko Ohara-Nemoto
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  5. Tomomi T. Baba
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  6. Takayuki K. Nemoto
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Correspondence to Takayuki K. Nemoto.

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Kobayakawa, T., Yamada, Si., Mizuno, A. et al. Single Nucleotide Polymorphism that Accompanies a Missense Mutation (Gln488His) Impedes the Dimerization of Hsp90. Protein J 28, 24–28 (2009). https://doi.org/10.1007/s10930-008-9160-1

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  • DOI: https://doi.org/10.1007/s10930-008-9160-1

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