Voet & Voet, Biochemistry

Intracellular Pathogens

Extracellular Pathogens

Acquired immunity depends on many specific protein-protein interactions

• Antibody - Antigen

• Cytotoxic T-cell receptor - MHC class I protein/peptide complex

• Helper T-cell receptor - MHC class II protein/peptide complex

Part 1: Antigen Specific

Voet & Voet, Biochemistry

Acquired immunity depends on non-specific protein-peptide interactions

• MHC class II - peptides generated in the endosome/lysosome (antigens of extracellular origin) recognized by helper T cells

• MHC class I - peptides generated in the cytoplasm (antigens of intracellular origin) recognized by cytotoxic T cells

StructuralBreathing

EndoproteolyticCleavage and

MHCII Binding

ExoproteolyticTrimming

Presentation

N C N C

C

C

C

C

N

NN

C

N

N

1

2

3

Antigen-presenting cell

T cell

Antigen-presenting cell

Antigen Internalizatione.g., via IgG receptor

Endosome/Lysosome

Antigen Processing and Presentation to Helper T-cell

Peptides bind to MHC Class II molecules in a common polyproline II conformation

Jardetzky et al., PNAS 93: 734-738 (1996)

Antigen Recognition by Antibodies (Ab) and T-cell Receptors (TCR)

• Surface area ~ 2x750 Å2

• > 50% hydrophobic

• 1-2 H-bonds

• Epitope discontinuous in antigen (Ag) sequence

• Surface area ~ 2x1000 Å2

• Ag peptide contributes only 40% of surface area

• Epitope continuous in Ag sequence

• Otherwise similar to Ab - Ag recognition

Ab - Ag TCR – MHC/peptide

Peptide Binding by Major Histocompatibility Complex (MHC)

Antigen-presenting Proteins

• Peptides of intracellular origin

• Peptides 9-10 residues long

• Deep pockets bind peptide sidechains

• Deep pockets bind peptide N- and C-termini

• Peptides of extracellular origin

• Peptides 15 residues or longer

• Shallow pockets bind peptide sidechains

• Peptide termini free

• H-bonds to peptide backbone

MHC I MHC II

• IgG receptor - IgG

• MHC class II protein - CD4

• MHC class I protein - CD8

• IL-2 - CD25

• TNF - TNF receptor

Part 2: Transport/Immunoregulatory(a few examples)

Acquired immunity depends on many specific protein-peptide interactions

The efficiency of antigen processing may control the T-cell cytokine profile for a given epitope by the size

of its “immunological synapse”

Grakoui et al., Science 285: 221-227 (1999)