PPS 96' - Quaternary Structure - Overview

(Logo) Quaternary Structure - Overview

IndexIndex to Course Material IndexIndex to Section 11

Quaternary structure is that level of form in which units of tertiary structure (separate polypeptide chains) aggregate to form homo- or hetero- multimers. This is found to be remarkably common, especially in the case of enzymes. The prokaryotic biosynthesis of tryptophan provides interesting examples which fall into each of the categories below. (See also Branden & Tooze `Introduction to Protein Structure' pub.Garland)

Covalently-Connected Tertiary Domains

The mosaic proteins are an example we've already come across, where the domains are usually formed as modules covalently `strung together' on a single polypeptide chain. The individual chains of antibodies are like this, strings of immuno-globulin domains. However, light and heavy chains then combine to produce hetero-multimers, which may even associate into higher complexes, as with IgM.
(If necessary refer to the page on mosaic proteins in the previous chapter, which includes a discussion of immunoglobulins.)

In the case of the single polypeptide chain of pyruvate kinase there are four domains; the central TIM-barrel is the catalytic domain, whereas the other three play no direct role in enzymatic activity. However, the small N-terminal domain of 42 residues is involved in inter-subunit contacts when four copies associate to form a homo-tetramer.

1pyk (44Kb) [Bbk|BNL|ExP|Waw|Hal]

E.coli produces a bifunctional enzyme which performs both the isomerisation of phospho-ribosyl anthranilate (residues 256 - 452) AND the synthesis of indole-glyceryl phosphate (residues 1 - 255), two steps in tryptophan biosynthesis. It comprises two very similar eight-stranded alpha/beta barrels, each barrel acting as a separate enzyme.

pdb file 1pii (359Kb) [Bbk|BNL|ExP|Waw|Hal].


In this case we see different tertiary domains aggregating together to form a unit. We've already seen an example in the case of the membrane-embedded photoreaction centre.

Sometimes, we find that several domains are found in a single enzyme complex, either in a single polypeptide chain, or as an association of separate chains.

Often the domains have related functions, for instance, where one domain will be responsible for binding, another for regulation, and a third for enzymatic activity. Take a glimpse at a delightful study of cellobiohydrolase , by Lauri Kuutti and at the Center for Scientific Computing, Finland.
(You also may want to re-visit the material on the photoreaction centre.)

Two (further) steps in the biosynthetic pathway of tryptophan (in S.typhimirium) are catalysed by tryptophan synthase which consists of two separate chains, designated alpha and beta, each of which is effectively a distinct enzyme. The biologically active unit is a hetero-tetramer comprised of 2 alpha and 2 beta units. Again you will recognise the TIM-barrel fold. Study the text-head of the pdb file.

tryptophan synthase 1wsy (406Kb)[Bbk|BNL|ExP|Waw|Hal]

We sometimes find slightly different versions of the same protein associating. Thus, haemoglobin has both an A-chain and a B-chain, which come together to form a hetero-dimer. Two copies of this then associate to form the normal haemoglobin tetramer; which is equivalent to an A-dimer associating with a B-dimer.

Allostery in haemoglobin will be described in the following chapter on Protein Interactions.


It is far more common to find copies of the same polypeptide chain associating non-covalently. Such complexes are usually, though not always symmetrical. Because proteins are inherently asymmetrical objects, the multimers almost always exhibit rotational symmetry about one or more axes. The majority of the enzymes of the metabolic pathways seem to aggregate in this way, forming dimers, trimers, tetramers, pentamers, hexamers, octamers, decamers, dodecamers, (or even tetradecamers in the case of the chaperonin GroEl; material on chaperonins will appear in a later Section of the course).

The reason for this is now thought to be the allosteric cooperativity that results in increased catalytic efficiency, effectively a `sharing' of the small conformational changes that accompany substrate binding and catalytic activity. A good well-studied example is the `breathing motion' observed in the haemoglobin tetramer.

Allostery in haemoglobin will be described in the following chapter on Protein Interactions.

Another interesting case study is found with the growth factors where we see dimers formed in 3 different ways, corresponding to two-fold axes in different directions.

(Diagrams and further information can be found at Judith Murray-Rust's Neurotrophic Factors page.)

We usually find that hetero and especially homo-multimers exhibit symmetry, a subject worthy of study in itself; covered elsewhere in this section.

Examples of symmetrical enzyme multimers in the form usually found in cells have been especially prepared and archived at Brookhaven in a directory dedicated to these biological units. It may be accessed by anonymous ftp to ftp.pdb.bnl.gov and going to directory /user_group/biological_units/; or access ftp://pdb.pdb.bnl.gov/user_group/biological_units/ with your WWW browser. The contents and associated README are worth a look.

The entries in the PDB biological units directory may be arranged to MIME-invoke a molecular viewer such as RasMol by entering the appropriate 4-letter code (in place of ****) into a URL of the form


There are other examples where dimerisation is necessary to actually create the active site of the enzyme in question. Instances of this include, for example,

Larger Structures

The molecular machinery of the cell and indeed of assemblies of cells, rely on or are controlled by large multimeric assemblies of proteins, nucleic acids, lipids, and sugars. Examples of these kinds of assemblies (fibers, filaments and viruses) are described in the Larger Assemblies section.

Fiberous proteins are very elongated and interact to form long strong fibers. The extracellular matrix is an example of a fiberous protein (collagen) complex.

Filamentous proteins are globular and assemble into long tubules or filaments. The cell cytoskeleton controls cell morphology and intra-cellular transport and contains two such assemblies: microtubules and actin filaments.

Viruses are large assemblies of proteins, nucleic acids and sometimes lipids. They perform a wide range of functions from replication to membrane fusion which are made possible only by their diverse multimeric nature.

If you have MAGE installed and configured for Chemical MIME, you can view the Branden and Tooze, Protein Science and Protein Tourist Kinemages, some of which are relevant to this material. Again, refer to the Technology Page if necessary. There are some links to appropriate Kinemages within this chapter.
IndexIndex to Course Material IndexIndex to Section 11

Last updated 28th Jun '96