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Role of the ubiquitin-like modifier FAT10 in protein degradation and ...

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Contents<br />

Acknowledgements 3<br />

Summary / Zusammenfassung 4<br />

English . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4<br />

Deutsch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6<br />

Introduction 9<br />

Prote<strong>in</strong> Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9<br />

The Ubiquit<strong>in</strong>-Proteasome-System . . . . . . . . . . . . . . . . . . . . . . . 10<br />

The Proteasome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10<br />

The 20S Proteasome . . . . . . . . . . . . . . . . . . . . . . . . 10<br />

The 26S Proteasome . . . . . . . . . . . . . . . . . . . . . . . . 11<br />

Ubiquit<strong>in</strong> <strong>and</strong> Ubiquit<strong>in</strong>-Like Prote<strong>in</strong>s . . . . . . . . . . . . . . . . . . 14<br />

Ubiquit<strong>in</strong> . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14<br />

Ubiquit<strong>in</strong>-Like Prote<strong>in</strong>s . . . . . . . . . . . . . . . . . . . . . . 18<br />

Ubiquit<strong>in</strong>-Like Modifiers . . . . . . . . . . . . . . . . . . . . . . 18<br />

<strong>FAT10</strong> . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21<br />

Ubiquit<strong>in</strong> Doma<strong>in</strong> Prote<strong>in</strong>s . . . . . . . . . . . . . . . . . . . . 24<br />

NUB1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26<br />

The Autophagy-Lysosome System . . . . . . . . . . . . . . . . . . . . . . . . 28<br />

Misfolded Prote<strong>in</strong> Stress, Aggresomes <strong>and</strong> <strong>the</strong> Connection between Au-<br />

tophagy <strong>and</strong> <strong>the</strong> UPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29<br />

HDAC6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33<br />

Chapter 1: The UBA doma<strong>in</strong>s <strong>of</strong> NUB1L are required for b<strong>in</strong>d<strong>in</strong>g but not for<br />

accelerated <strong>degradation</strong> <strong>of</strong> <strong>the</strong> <strong>ubiquit<strong>in</strong></strong>-<strong>like</strong> <strong>modifier</strong> <strong>FAT10</strong> 36<br />

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37<br />

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38<br />

Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40<br />

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51<br />

Experimental Procedures . . . . . . . . . . . . . . . . . . . . . . . . . 56<br />

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