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Related Experiment Videos

Coordinated ATP hydrolysis by the Hsp90 dimer.

K Richter1, P Muschler, O Hainzl

  • 1Institut für Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstr. 4, Garching 85747, Germany.

The Journal of Biological Chemistry
|July 7, 2001
PubMed
Summary

Heat shock protein 90 (Hsp90) dimerization and ATP hydrolysis are linked. Cooperative interactions in Hsp90

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Area of Science:

  • Molecular Biology
  • Biochemistry
  • Structural Biology

Background:

  • Heat shock protein 90 (Hsp90) is a molecular chaperone.
  • Hsp90 possesses a unique N-terminal ATP binding site, classifying it within the GHKL family of ATP-hydrolyzing enzymes.
  • Structural data on ATP-induced conformational changes are available for some GHKL family members but lacking for Hsp90.

Purpose of the Study:

  • To investigate the correlation between dimerization and ATP hydrolysis in Hsp90.
  • To elucidate the role of N-terminal domains in Hsp90's ATPase activity and conformational changes.

Main Methods:

  • Determination of the dimerization constant for wild-type (WT) Hsp90.
  • Formation and analysis of heterodimers between WT Hsp90 and Hsp90 fragments or mutants lacking ATP binding domains.
  • Measurement of ATPase activity in various Hsp90 constructs and heterodimers.

Main Results:

  • WT Hsp90 has a dimerization constant of 60 nm.
  • Heterodimers formed with ATP-binding domain-lacking fragments showed similar dimerization constants but reduced ATPase activity compared to WT Hsp90.
  • A point mutant unable to bind ATP, when forming heterodimers with WT Hsp90, retained WT ATPase activity, suggesting ATP binding is not required for inter-domain stimulation.

Conclusions:

  • Cooperative interactions within the N-terminal domains of Hsp90 are crucial for activating its ATPase activity.
  • Dimerization and N-terminal domain contact formation may not strictly depend on ATP binding to both Hsp90 protomers.
  • A mechanism is proposed where ATP hydrolysis is coupled to the opening-closing conformational movements of the Hsp90 chaperone.

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