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Protein folding & Chaperones

Protein folding & Chaperones. Characteristics of Folded State. Tight packing – compact Sequence determined/environment modulated Families and symmetry Each sequence  unique structure Native state is thermodynamically stable Lowest energy. Physics of Folding. Entropy drives towards this

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Protein folding & Chaperones

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  1. Protein folding & Chaperones

  2. Characteristics of Folded State • Tight packing – compact • Sequence determined/environment modulated • Families and symmetry • Each sequence  unique structure • Native state is thermodynamically stable • Lowest energy

  3. Physics of Folding • Entropy drives towards this • HB exposed • Enthalpy drives towards this • HB interactions • H bonding • Ionic interactions Free Energy is the Difference • Folded state is more stable

  4. Unfolded bury core  2o Molten globule 3o 4o protein HB aa (loose 3o) (breathing) Steps of Folding < ms Up to 1s

  5. Why won’t it fold? Most common obstacles to a native fold: • Aggregation • Non-native disulfide bridge formation • Isomerization of proline

  6. Energy Funnel for Folding • Multiple folding pathways can occur • Model this with energy funnel

  7. Chaperonins / Heat Shock Proteins HSPs help proteins fold by preventing aggregation • Recognize only unfolded proteins • Not specific • Recognizes exposed HB patches • Prevent aggregation of unfolded or misfolded proteins • HSP70 • Assembly & disassembly of oligomers • Regulate translocation to ER • HSP60 (GroEL) & HSP10 (GroES) • Work as a complex

  8. GroEL • Each subunit • Apical (a/b motif) • Opening of chaperone to unfolded protein • Flexible • HB • Intermediate (a helices) • Allow ATP and ADP diffusion • Flexible hinges • Equatorial (a helices) • ATP binding site • Stabilizes double ring structure • Central cavity up to 90Å diam. • 7 subunits in one ring • 2 rings back to back

  9. GroES • Cap to the GroEL • Each subunit • b sheet • b hairpin (roof) • Mobile loop (int w/ GroEL) • 7 subunits in functional molecule

  10. GroEL+ GroES work together • GroEL makes up a cylinder • Each side has 7 identical subunits • Each side can accommodate one unfolded protein • 1 GroES binds to one side of GroEL at a time • Allosteric inhibition at other site • One side of cylinder is actively folding protein at a time

  11. GroEL/ATP complex at side A • Bind GroES on this side 7 ATP7 ADP this side has a wider cavity but closed top other side has smaller cavity and open top • Side B ring binds unfolded protein GroES falls off of side A ADP falls off of side A • Side B ring binds 7 ATPs • GroES binds GroEL/ATP 7 ATP7 ADP protein folding occurs • Side A ring binds 7 ATPs protein folding occurs 7 ATP7 ADP (side A) 7 ADP & GroES (side B) falls off • Side A ring binds next unfolded protein

  12. Mechanism of Chaperonin Function • Switch side of ATP binding each time • Switch side of GroES binding for each folding rxn • Switch side of protein docking for each folding rxn Fink, Chaperone Mediated Folding, Physiological Reviews, 1999

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