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.
The function of a protein (except as food) depends on its tertiary structure. If this is disrupted, the protein is said to be denatured [Discussion], and it loses its activity.
A mutation in the gene encoding a protein is a frequent cause of altered tertiary structure.
- denatured enzymes lose their catalytic power
- denatured antibodies can no longer bind antigen
The many hydrogen bonds that can form between the polypeptide backbones in the beta conformation suggests that this is a stable secondary structure potentially available to many proteins and so a tendency to form insoluble aggregates is as well. Avoidance of amyloid formation may account for the large investment in the cell in
as well as the crucial importance of particular amino acid side chains in maintaining a globular, and hence soluble, tertiary structure.
- The mutant versions of proteins may fail to reach their proper destination in the cell and/or be degraded.
- 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
- 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.
- 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.,
can form insoluble amyloid deposits in humans.
The tertiary structure of many proteins is built from several domains.
Often each domain has a separate function to perform for the protein, such as:
In some (but not all) cases, each domain in a protein is encoded by a separate exon in the gene encoding that protein.
In the histocompatibility molecule shown here ,
- three domains
- α2, and
- α3 are each encoded by its own exon.
- Two additional domains (not shown here but that can be seen at this link),
are also encoded by separate exons.
- a transmembrane domain and a
- cytoplasmic domain
- (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]
31 August 2013