The Three-Dimensional Structure of Proteins Recap

c-Fos:c-Jun dimer—a bZIP transcription factor 1 Leucine Zipper Motif c-Fos:c-Jun dimer—a bZIP transcription factor leucines

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

2-3 Secondary structure Tertiary structure

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

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)

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.

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.

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.

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.

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.

Osteogenesis Imperfecta Collagen Mutation Osteogenesis Imperfecta 12 Gly988Cys

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

“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.