Prions and Protein Misfolding

BICH 107

GENE 105

Kuru

• Discovered in Papua New Guinea in early 1900's

• "Trembling with fear"

• Characterized by headaches, joint pain, shaking of limbs, progressive dementia

• Always fatal

TSE

Transmissible Spongiform Encephalopathy

• Kuru (human)• Creutzfeldt-Jacob Disease (human)• Bovine Spongiform Encephalopathy (cow)• Scrapie (sheep)• Chronic Wasting Disease (elk and deer)

Prions

• Rich in protein• No detectable nucleic acid• Resistant to treatments that destroy nucleic acids• Stanley Prusiner - Nobel Prize in Physiology or

Medicine (1997)

DNA RNA Protein

Information Flow in Cells

Transcription Translation

Protein Primary Structure

H-Bonds in DNA

-Helix Secondary Structure

-sheet Secondary Structure

Two Types of -Sheet

Triose-Phosphate Isomerase

Triose-Phosphate Isomerase 2

Solution Structure of PrPc

Zahn, Ralph et al. (2000) Proc. Natl. Acad. Sci. USA 97, 145-150

Solution Structure of A

Structure of A fibril

Petkova, Aneta T. et al. (2002) Proc. Natl. Acad. Sci. USA 99, 16742-16747