Tertiary Structure

Tertiary structure refers to the three-dimensional structure of the entire polypeptide chain.

The images (courtesy of Dr. D. R. Davies) represent the tertiary structure of the antigen-binding portion of an antibody molecule. Each circle represents an alpha carbon in one of the two polypeptide chains that make up this protein. (The filled circles at the top are amino acids that bind to the antigen.) Most of the secondary structure of this protein consists of beta conformation, which is particularly easy to see on the right side of the image.

Do try to fuse these two images into a stereoscopic (3D) view. I find that it works best when my eyes are about 18" from the screen and I try to relax so that my eyes are directed at a point behind the screen.

Where the entire protein or parts of a protein are exposed to water (e.g., in blood or the cytosol), hydrophilic R groups — including R groups with sugars attached [Link] — are found at the surface; hydrophobic R groups are buried in the interior.

Tertiary structure is important!

• denatured enzymes lose their catalytic power
• denatured antibodies can no longer bind antigen

• The mutant versions of proteins may fail to reach their proper destination in the cell and/or be degraded.
  Examples:
  • Most cases of cystic fibrosis are caused by failure of the mutant CFTR protein to reach its destination in the plasma membrane [More].
  • Diabetes insipidus is caused by improper folding of mutant versions of
    • V2 — the vasopressin (ADH) receptor or
    • aquaporin
  • Familial hypercholesterolemia is caused by failure of mutant low-density lipoprotein (LDL) receptors to reach the plasma membrane. [Discussion]
  • Osteogenesis imperfecta is caused by failure of mutant Type I collagen molecules to assemble correctly. [More]
• Mutant proteins may aggregate forming insoluble, nonfunctional deposits. This is particularly likely if the mutation causes hydrophobic R groups to be displayed at the surface of the molecule rather than in its interior and/or triggers the formation of the beta conformation in a formerly-soluble protein. Insoluble aggregates of any protein dominated by beta conformation are called amyloid.
  Examples:
  • Bovine spongiform encephalopathy (BSE) ("mad cow") disease and the human version — Creutzfeldt-Jakob disease (CJD) — are characterized by amyloid deposits in the brain of a mutant version of the prion protein.

    The normal protein has lots of alpha helical regions and is soluble. In the mutant version, the alpha helix is converted into beta conformation and the protein becomes insoluble.

    Curiously, tiny amounts of the mutant version can trigger the alpha-to-beta conversion in the normal protein. Thus the mutant version can be infectious. There have been several cases in Europe of people ill with Creutzfeldt-Jakob disease that may have acquired it from ingesting tiny amounts of the mutant protein in their beef.

  • A number of other proteins altered by a point mutation in the gene encoding them, e.g.,
    • fibrinogen
    • lysozyme
    • transthyretin (a serum protein that transports thyroxin and retinol (vitamin A) in the blood)
    can form insoluble amyloid deposits in humans.

• chaperones
• proteasomes

Protein Domains

The tertiary structure of many proteins is built from several domains.

• binding a small ligand (e.g., a peptide in the molecule shown here)
• spanning the plasma membrane (transmembrane proteins)
• containing the catalytic site (enzymes)
• DNA-binding (in transcription factors)
• providing a surface to bind specifically to another protein [Example]

In some (but not all) cases, each domain in a protein is encoded by a separate exon in the gene encoding that protein.

• three domains
  • α₁,
  • α₂, and
  • α₃ are each encoded by its own exon.
• Two additional domains (not shown here but that can be seen at this link),
  • a transmembrane domain and a
  • cytoplasmic domain
  are also encoded by separate exons.
• (β₂-microglobulin, "β₂m", is NOT a domain of this molecule. It is a separate molecule that binds to the three alpha domains (red line and circle) by noncovalent forces only. The complex of these two proteins is an example of quaternary structure.)

This image (courtesy of P. J. Bjorkman from Nature 329:506, 1987) is a schematic representation of the extracellular portion of HLA-A2, a human class I histocompatibility molecule. It also illustrates two common examples of secondary structure: the stretches of beta conformation are represented by the broad green arrows (pointing N -> C terminal); regions of alpha helix are shown as helical ribbons. The pairs of purple spheres represent the disulfide bridges.

A correspondence between exons and domains is more likely to be seen in recently-evolved proteins. Presumably, "exon shuffling" during evolution has enabled organisms to manufacture new proteins, with new functions, by adding exons from other parts of the genome to encode new domains (rather like Lego® pieces). [Link to gene duplication]