Protein Folding

Co-translational Folding at the Ribosome Exit Tunnel

Summary

The ribosomal exit tunnel is a 100Å channel through which nascent polypeptides emerge. Its geometry permits α-helix formation and affects folding kinetics, while the vestibule region allows early tertiary contacts.

Key Points

  • 1Tunnel is ~100Å long, accommodating 30-40 amino acids
  • 2α-Helix formation occurs inside the tunnel
  • 3Vestibule allows early tertiary contacts and small domain folding
  • 4Stalling sequences enable regulatory checkpoints
  • 5Exit site couples to chaperones and targeting machinery

The ribosomal exit tunnel shapes the earliest stages of protein folding, acting as a conduit that influences nascent chain conformation before the protein enters the cytosol.

Tunnel Architecture

Dimensions

- Length: ~100 Å (80-100 Å depending on species)

- Width: Varies from ~10 Å at constriction to ~20 Å at vestibule

- Volume: Accommodates 30-40 amino acids

Key Regions

1. Upper tunnel: Narrow, lined by ribosomal proteins L4 and L22

2. Constriction site: Narrowest point (~10 Å), regulatory checkpoint

3. Lower tunnel/vestibule: Widens near exit, allows secondary structure

Composition

- Primarily 23S rRNA (bacteria) / 28S rRNA (eukaryotes)

  • Ribosomal proteins L4, L22, L23, L29 contribute
  • Electronegative character from rRNA phosphates
  • Folding Inside the Tunnel

    α-Helix Formation

  • Tunnel dimensions permit α-helix formation (diameter ~12 Å)
  • Helices can form 30-40 residues from the PTC
  • Compaction detected by force measurements and cryo-EM
  • Tertiary Contacts

  • Limited by tunnel constraints
  • Vestibule region allows initial tertiary interactions
  • Small domains (zinc fingers) can fold near exit
  • Folding Zones

    - Zone 1 (PTC region): Extended chain only

    - Zone 2 (upper tunnel): Helix nucleation possible

    - Zone 3 (vestibule): Secondary structure, early tertiary contacts

    - Zone 4 (exit): Full domain folding possible

    Tunnel-Nascent Chain Interactions

    - Electrostatic: Positively charged residues interact with rRNA

    - Stalling sequences: Specific peptides (SecM, VemP) arrest translation

    - Small molecules: Macrolide antibiotics bind tunnel, blocking transit

    Functional Implications

    Vectorial Folding

  • N-terminus folds before C-terminus is synthesized
  • Prevents premature domain interactions
  • Multi-domain proteins benefit most
  • Chaperone Coupling

  • Exit site is decorated with chaperones (Trigger Factor, NAC)
  • Provides seamless handoff from tunnel to chaperone
  • Membrane Targeting

  • Signal sequences are recognized at tunnel exit
  • SRP binds nascent chains for ER targeting