Protein Misfolding

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Protein Misfolding Protein-folding Diseases

• Conformational Transitions Switches in Proteins

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Since Anfinsen.
1) 1 dictates 2 dictates 3 dictates function
But what if 3 (or context) dictates/influences
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2) Only two states N (native) and U (unfolded)
But weve accepted MG (molten globule states
3) One amino-acid sequence one structure
But we already know about conformation transitions
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Familiar (?) examples of conformational
transitions in proteins

• Tense and Relaxed states of haemoglobin
• Zymogen forms of the serine proteases
• Colicin in its interactions with membranes
• Influenza haemagglutinin
• Amyloid prion diseases

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A conformational switch
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Influenza hemagglutinin (HA)
All good text books Skehel Wiley (2000) Ann
Rev Biochem 69 531-569
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Schematics
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Sequence duality
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Context-dependent 2 structure

• Previously 2 determined by 1(2 preferences
  HP patterns).
• 1981 Kabsch Sander(analysis of conserved
  pentamers in PDB)
• 1996 Minor Kim(chameleon peptide)
• 1997 Dalal Regan(Janus protein)

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Kabsch Sander
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Chameleon

• Minor Kim (1996)Nature 380 730-734
• Designed a single sequence to be compatible with
  both a b structure.
• Experimental demonstration that context (in this
  case tertiary structure) can dictate secondary
  structure.

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Janus

• Dalal Regan (1997)Nature Struct Biol 4
  548-552 Folding Design 2 R71-R79
• See Qu. 7 on the PFF paper from Summer 2000.
• Transmuted protein G sequence to adopt ROP
  structure.

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Coiled Coils Helical Wheels
HPPHPPPHPPHPPP abcdefgabcdefg ?3???4??3???4?
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A little more sophisticatedsequence duality
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Helicity StabilityCircular Dichroism (CD)
Spectroscopy
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Time-dependent formation of b-structure
unfolding Template-aT
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The proof isin the EM
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Amyloid Prion

• Protein-folding diseases

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The common core of amyloid structures is
b-structured.
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Perplexing because of the variety of proteins
that form amyloid
JW Kelly (1996) Curr. Opin. Struct. Biol. 6 11-17
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So what does this mean?

• Perhaps sequence isnt important.AND/OR
• beta-amyloid structure is the resting place of
  all proteins?IF SO
• What prevents amyloid formation?