Protein quaternary structure

Protein quaternary structure[a] is the number and arrangement of multiple folded protein subunits in a multi-subunit complex. It includes organizations from simple dimers to large homooligomers and complexes with defined or variable numbers of subunits.[1] It can also refer to biomolecular complexes of proteins with nucleic acids and other cofactors.

Protein primary structureProtein secondary structureProtein tertiary structureProtein quaternary structure
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Interactive diagram of protein structure, using PCNA as an example. (PDB: 1AXC​)

Description and examplesEdit

Many proteins are actually assemblies of multiple polypeptide chains. The quaternary structure refers to the number and arrangement of the protein subunits with respect to one another.[2] Examples of proteins with quaternary structure include hemoglobin, DNA polymerase, and ion channels.

Enzymes composed of subunits with diverse functions are sometimes called holoenzymes, in which some parts may be known as regulatory subunits and the functional core is known as the catalytic subunit. Other assemblies referred to instead as multiprotein complexes also possess quaternary structure. Examples include nucleosomes and microtubules. Changes in quaternary structure can occur through conformational changes within individual subunits or through reorientation of the subunits relative to each other. It is through such changes, which underlie cooperativity and allostery in "multimeric" enzymes, that many proteins undergo regulation and perform their physiological function.

The above definition follows a classical approach to biochemistry, established at times when the distinction between a protein and a functional, proteinaceous unit was difficult to elucidate. More recently, people refer to protein–protein interaction when discussing quaternary structure of proteins and consider all assemblies of proteins as protein complexes.


The number of subunits in an oligomeric complex is described using names that end in -mer (Greek for "part, subunit"). Formal and Greco-Latinate names are generally used for the first ten types and can be used for up to twenty subunits, whereas higher order complexes are usually described by the number of subunits, followed by -meric.

  • 13 = tridecamer
  • 14 = tetradecamer
  • 15 = pentadecamer*
  • 16 = hexadecamer
  • 17 = heptadecamer*
  • 18 = octadecamer
  • 19 = nonadecamer
  • 20 = eicosamer
  • 21 = 21-mer
  • 22 = 22-mer
  • 23 = 23-mer*
  • etc.
*No known examples

Although complexes higher than octamers are rarely observed for most proteins, there are some important exceptions. Viral capsids are often composed of multiples of 60 proteins. Several molecular machines are also found in the cell, such as the proteasome (four heptameric rings = 28 subunits), the transcription complex and the spliceosome. The ribosome is probably the largest molecular machine, and is composed of many RNA and protein molecules.

In some cases, proteins form complexes that then assemble into even larger complexes. In such cases, one uses the nomenclature, e.g., "dimer of dimers" or "trimer of dimers", to suggest that the complex might dissociate into smaller sub-complexes before dissociating into monomers.


Protein quaternary structure can be determined using a variety of experimental techniques that require a sample of protein in a variety of experimental conditions. The experiments often provide an estimate of the mass of the native protein and, together with knowledge of the masses and/or stoichiometry of the subunits, allow the quaternary structure to be predicted with a given accuracy. It is not always possible to obtain a precise determination of the subunit composition for a variety of reasons.

The number of subunits in a protein complex can often be determined by measuring the hydrodynamic molecular volume or mass of the intact complex, which requires native solution conditions. For folded proteins, the mass can be inferred from its volume using the partial specific volume of 0.73 ml/g. However, volume measurements are less certain than mass measurements, since unfolded proteins appear to have a much larger volume than folded proteins; additional experiments are required to determine whether a protein is unfolded or has formed an oligomer.

Intragenic complementationEdit

When multiple copies of a polypeptide encoded by a gene form a quaternary complex, this protein structure is referred to as a multimer.[3] When a multimer is formed from polypeptides produced by two different mutant alleles of a particular gene, the mixed multimer may exhibit greater functional activity than the unmixed multimers formed by each of the mutants alone. In such a case, the phenomenon is referred to as intragenic complementation (also called inter-allelic complementation). Intragenic complementation appears to be common and has been studied in many different genes in a variety of organisms including the fungi Neurospora crassa, Saccharomyces cerevisiae and Schizosaccharomyces pombe; the bacterium Salmonella typhimurium; the virus bacteriophage T4,[4] an RNA virus,[5] and humans.[6] The intermolecular forces likely responsible for self-recognition and multimer formation were discussed by Jehle.[7]


Some bioinformatics methods were developed for predicting the quaternary structural attributes of proteins based on their sequence information by using various modes of pseudo amino acid composition.[8][9][10]

Direct mass measurement of intact complexesEdit

Direct size measurement of intact complexesEdit

Indirect size measurement of intact complexesEdit

Methods that measure the mass or volume under unfolding conditions (such as MALDI-TOF mass spectrometry and SDS-PAGE) are generally not useful, since non-native conditions usually cause the complex to dissociate into monomers. However, these may sometimes be applicable; for example, the experimenter may apply SDS-PAGE after first treating the intact complex with chemical cross-link reagents.

Protein–protein interactionsEdit

Proteins are capable of forming very tight complexes. For example, ribonuclease inhibitor binds to ribonuclease A with a roughly 20 fM dissociation constant. Other proteins have evolved to bind specifically to unusual moieties on another protein, e.g., biotin groups (avidin), phosphorylated tyrosines (SH2 domains) or proline-rich segments (SH3 domains). Protein-protein interactions can be engineered to favor certain oligomerization states.[11]


Direct interaction of two nascent proteins emerging from nearby ribosomes appears to be a general mechanism for oligomer formation.[12] Hundreds of protein oligomers were identified that assemble in human cells by such an interaction.[12] The most prevalent form of interaction was between the N-terminal regions of the interacting proteins. Dimer formation appears to be able to occur independently of dedicated assembly machines.

See alsoEdit


  1. ^ Here quaternary means "fourth-level structure", not "four-way interaction". Etymologically quartary is correct: quaternary is derived from Latin distributive numbers, and follows binary and ternary; while quartary is derived from Latin ordinal numbers, and follows secondary and tertiary. However, quaternary is standard in biology.


  1. ^ Berg JM, Tymoczko JL, Stryer L (2002). "Section 3.5Quaternary Structure: Polypeptide Chains Can Assemble Into Multisubunit Structures". Biochemistry (5. ed., 4. print. ed.). New York, NY [u.a.]: W. H. Freeman. ISBN 0-7167-3051-0.
  2. ^ Chou KC, Cai YD (November 2003). "Predicting protein quaternary structure by pseudo amino acid composition". Proteins. 53 (2): 282–9. doi:10.1002/prot.10500. PMID 14517979. S2CID 23979933.
  3. ^ Crick FH, Orgel LE (January 1964). "The theory of inter-allelic complementation". Journal of Molecular Biology. 8: 161–5. doi:10.1016/s0022-2836(64)80156-x. PMID 14149958.
  4. ^ Bernstein H, Edgar RS, Denhardt GH (June 1965). "Intragenic complementation among temperature sensitive mutants of bacteriophage T4D". Genetics. 51 (6): 987–1002. doi:10.1093/genetics/51.6.987. PMC 1210828. PMID 14337770.
  5. ^ Smallwood S, Cevik B, Moyer SA (December 2002). "Intragenic complementation and oligomerization of the L subunit of the sendai virus RNA polymerase". Virology. 304 (2): 235–45. doi:10.1006/viro.2002.1720. PMID 12504565.
  6. ^ Rodríguez-Pombo P, Pérez-Cerdá C, Pérez B, Desviat LR, Sánchez-Pulido L, Ugarte M (June 2005). "Towards a model to explain the intragenic complementation in the heteromultimeric protein propionyl-CoA carboxylase". Biochimica et Biophysica Acta. 1740 (3): 489–98. doi:10.1016/j.bbadis.2004.10.009. PMID 15949719.
  7. ^ Jehle H (September 1963). "Intermolecular forces and biological specificity". Proceedings of the National Academy of Sciences of the United States of America. 50 (3): 516–24. Bibcode:1963PNAS...50..516J. doi:10.1073/pnas.50.3.516. PMC 221211. PMID 16578546.
  8. ^ Chou KC, Cai YD (November 2003). "Predicting protein quaternary structure by pseudo amino acid composition". Proteins. 53 (2): 282–9. doi:10.1002/prot.10500. PMID 14517979. S2CID 23979933.
  9. ^ Zhang SW, Chen W, Yang F, Pan Q (October 2008). "Using Chou's pseudo amino acid composition to predict protein quaternary structure: a sequence-segmented PseAAC approach". Amino Acids. 35 (3): 591–8. doi:10.1007/s00726-008-0086-x. PMID 18427713. S2CID 689955.
  10. ^ Xiao X, Wang P, Chou KC (2009). "Predicting protein quaternary structural attribute by hybridizing functional domain composition and pseudo amino acid composition". Journal of Applied Crystallography. 42: 169–173. doi:10.1107/S0021889809002751.
  11. ^ Ardejani MS, Chok XL, Foo CJ, Orner BP (May 2013). "Complete shift of ferritin oligomerization toward nanocage assembly via engineered protein-protein interactions". Chemical Communications. 49 (34): 3528–30. doi:10.1039/C3CC40886H. PMID 23511498.
  12. ^ a b Bertolini M, Fenzl K, Kats I, Wruck F, Tippmann F, Schmitt J, Auburger JJ, Tans S, Bukau B, Kramer G. Interactions between nascent proteins translated by adjacent ribosomes drive homomer assembly. Science. 2021 Jan 1;371(6524):57-64. doi: 10.1126/science.abc7151. PMID: 33384371

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