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Glycobiology Advance Access published online on May 28, 2003
Glycobiology, doi:10.1093/glycob/cwg081
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Submitted on November 8, 2002
Revised on May 5, 2003
Accepted on May 7, 2003

© 2003 Oxford University Press

ORIGINAL ARTICLES

Modulation of prion protein structural integrity by geldanamycin

H.-J. Ochel 1*, G. Gademann 1, J. Trepel 2, L. Neckers 2

1 Otto-von-Guericke-University, Medical Faculty, Clinic for Radiation Therapy, Radiobiological Laboratory, Leipziger Str. 44, 39120 Magdeburg, Germany
2 National Institutes of Health, National Cancer Institute, Medicine Branch, Tumor Cell Biology Section, 9610 Medical Center Drive St. 300, Rockville, MD 20850

* To whom correspondence should be addressed. E-mail: Hans-Joachim.Ochel{at}medizin.uni-magdeburg.de.

Abstract

The cellular prion protein PrPc is of crucial importance for the development of neurodegenerative diseases called transmissible spongiform encephalopathies. We investigated if the function of members of the HSP90 family is required for the integrity of the normal, non-pathogenic prion protein called PrPc. Eukaryotic cells were treated with the structurally unrelated HSP90-inhibitors geldanamycin (GA) or radicicol (RC). In either case the cellular prion protein was induced and exhibited faster migrating bands on Western blot analysis, while geldampicin (GE), an analog of geldanamycin known not to bind to HSP90, had no effect. Ongoing protein- and messenger RNA synthesis during treatment were found to be necessary for the appearance of these bands. Cotreatment with tunicamycin abrogated any effect of HSP90-inhibitors on the cellular prion protein. Finally, enzymatic deglycosylation with Peptide:N-Glycosydase F of the normal prion protein as well as the variant induced by benzoquinone ansamycins resulted in very similar band-patterns. These experiments indicate that either altered glycosylation or a change in conformation or both are involved in the induction of faster migrating bands by Hsp90-inhibitors. Thus, the inhibition of the function of members of the HSP90 family of molecular chaperones results in profound changes in the physico-chemical properties of PrPc.


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