1. The Three-Dimensional Structure of Proteins
Recap

2. c-Fos:c-Jun dimer—a bZIP transcription factor1
Leucine Zipper Motif
c-Fos:c-Jun dimer—a bZIP transcription factor
leucines

3. Example: antibody (12 domains)
2-3
Enzyme cleavage
Fc fragment
Fab fragment
Domain:
-- folded structure
(tertiary)
-- includes side chains
-- hydrophobic core
-- hydrophilic surface
-- folds independently
-- stable when isolated
Fold:
--the peptide backbone:
the secondary structure of a domain

4. 2-3
Secondary structure
Tertiary structure

5. 4-5
Folds of two immunoglobulin domains
Domain Stabilizing forces:
Non-covalent
H-bonding
hydrophobic forces
van der Waals forces
ionic interactions
Covalent: -S-S- bonds
Same for antibody-antigen binding

6. 6
X-ray structure of hemoglobin
Arrow in circle: O2 binding site.
No path for O2
Movements open up path

7. 7-8
Amino Acid Mutations and Protein Structure/Function
Hemoglobin Mutations
Hb Ann Arbor: α-chain Leu80Arg
(Leu in hydrophobic core. Arg couldn’t be buried.
Unstable structure)
HbE : β-chain Glu26Lys
(Glu on surface. Lys hydrophilic. Can substitute.
Only mild symptoms)

8. Alzheimer’s Amyloid β(1-42)
9-10
Aβ(1-42) in α-helical structure: nontoxic
Aβ(1-42) in β-structure: precipitates as fibrils, toxic
β-form more stable.
But the transition state energy is lower for going from I to the α-form than to the β-form, so the formation of the α-form is faster.

9. Alzheimer’s Amyloid β(1-42)
9-10
Aβ(1-42) in α-helical structure: nontoxic
Aβ(1-42) in β-structure: precipitates as fibrils, toxic
β-form more stable.
But the transition state energy is lower for going from I to the α-form than to the β-form, so the formation of the α-form is faster.

10. 11
Structure of Aβ(1-42)
Two fibers are connected to each other non-covalently.
Each fiber has stacked Aβ(15-42) peptides.
Each of their 4 β-strands are parallel and in register with adjacent peptide β-strands, making H-bonds.
New peptides are added in the direction of the axis.
The β-strands wrap around a hydrophobic core.

11. Each layer has two peptides.
One Layer: 11
Each layer has two peptides.
Each peptide has S-shaped polypeptide backbones.
Layer has 2-fold symmetry.
Residues 1-14 are partially disordered.
Non-covalent interaction between the 2 peptides.
Glycines have key role in allowing sharp tunes.

12. 11 The core of each layer contains hydrophobic amino acids (white).
The hydrophobic core runs throughout the fibril and also connects the two fibers.
The hydrophobic effect is the main driver of fibril formation and stability.
Hydrophilic amino acids are on the surface.

13. Osteogenesis Imperfecta
Collagen Mutation
Osteogenesis Imperfecta 12
Gly988Cys

14. 13
A polypeptide chain can rotate around the phi and psi bonds, but not around the peptide bond.

15. “Levinthal’s Paradox”
Protein Folding
“Levinthal’s Paradox” 14
For the peptide backbone only:
If protein folding were completely random:
For 140 peptide bonds, there are 280 total phi and psi bonds.
If there are 3 stable angles possible for each bond, the total possible conformations are:
3280
It’s not possible to sample all of the possibilities.
Therefore there are shortcuts to protein folding.