Analysis of the conformational dynamics of Hsp70 and Hsp90 chaperones [Elektronische Ressource] / presented by Christian Graf

Dissertation submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University of Heidelberg, Germany for the degree of Doctor of Natural Sciences presented by Diplom-Chemiker Christian Graf born in Saarbrücken Oral examination: 19.06.2008 Analysis of the Conformational Dynamics of Hsp70 and Hsp90 Chaperones Referees: PD Dr. Matthias P. Mayer Prof. Dr. Irmgard Sinning Meinen Eltern Table of contents TABLE OF CONTENTS I PUBLICATIONS FROM THIS THESIS V SUMMARY VII ZUSAMMENFASSUNG IX 1 INTRODUCTION 1 1.1 Protein Folding and Dynamics 1 1.2 Molecular Chaperones 3 1.2.1 The Hsp70 chaperone machinery 4 1.2.1.1 Cellular functions of Hsp70 4 1.2.1.2 Hsp70 structure 5 1.2.1.3 Hsp70 functional cycle 7 1.2.2 The Hsp90 chaperone machinery 10 1.2.2.1 Cellular functions of Hsp90 10 1.2.2.2 Hsp90 structure 12 1.2.2.3 Hsp90 chaperone cycle 16 1.2.2.4 Hsp90 inhibitors and cancer treatment 18 1.2.3 TPR Co-chaperones 20 1.2.3.1 Hsp70/Hsp90 organizing protein (Hop) 20 1.2.3.2 The E3 ubiquitin-ligase CHIP 21 1.3 Biomolecular Mass Spectrometry 23 1.4 Amide Hydrogen Exchange 27 1.4.1 Hydrogen exchange mechanism 27 1.4.2 Amide hydrogen exchange and mass spectrometry (HX-MS) 30 1.5 Aims of this thesis 32 2 RESULTS AND DISCUSSION 33 2.