Quaternary structure
Encyclopedia
In biochemistry
, quaternary structure is the arrangement of multiple folded
protein
or coiling protein molecules in a multi-subunit complex.
s. In addition to the tertiary structure
of the subunits, multiple-subunitproteins possess a quaternary structure, which is the arrangement into which the subunits assemble. Enzyme
s 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. Examples of proteins with quaternary structure include hemoglobin
, DNA polymerase
, and ion channel
s. Other assemblies referred to instead as multiprotein complexes also possess quaternary structure. Examples include nucleosome
s and microtubule
s. 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 complex
es.
ic 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.
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 machine
s 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.
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 determined whether a protein is unfolded or has formed an oligomer.
(see, e.g., refs.
).
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-linking reagents.
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).
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
, quaternary structure is the arrangement of multiple folded
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
or coiling protein molecules in a multi-subunit complex.
Description and examples
Many proteins are actually assemblies of more than one polypeptide chain, which in the context of the larger assemblage are known as protein subunitProtein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
s. In addition to the tertiary structure
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
of the subunits, multiple-subunit
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s 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. Examples of proteins with quaternary structure include hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
, DNA polymerase
DNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....
, and ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s. Other assemblies referred to instead as multiprotein complexes also possess quaternary structure. Examples include nucleosome
Nucleosome
Nucleosomes are the basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound around a histone protein core. This structure is often compared to thread wrapped around a spool....
s and microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
s. 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
Cooperative binding
In biochemistry, a macromolecule exhibits cooperative binding if its affinity for its ligand changes with the amount of ligand already bound.Cooperative binding is a special case of allostery. Cooperative binding requires that the macromolecule have more than one binding site, since 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
Protein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
when discussing quaternary structure of proteins and consider all assemblies of proteins as protein complex
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
es.
Nomenclature of quaternary structures
The number of subunits in an oligomerOligomer
In chemistry, an oligomer is a molecule that consists of a few monomer units , in contrast to a polymer that, at least in principle, consists of an unlimited number of monomers. Dimers, trimers, and tetramers are oligomers. Many oils are oligomeric, such as liquid paraffin...
ic 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.
|
Dodecamer Dodecameric is a term pertaining to protein quaternary structure, and describes a protein complex with 12 protein subunits . Dodecameric complexes can have a number of subunit 'topologies', but typically only a few of the theoretically possible subunit arrangements are observed in protein... |
|
|
* No known examples
Although complexes higher than octamers are rarely observed for most proteins, there are some important exceptions. Viral capsids
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
are often composed of multiples of 60 proteins. Several molecular machine
Molecular machine
A molecular machine, or nanomachine, is any discrete number of molecular components that produce quasi-mechanical movements in response to specific stimuli . The expression is often more generally applied to molecules that simply mimic functions that occur at the macroscopic level...
s are also found in the cell, such as the proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
(four heptameric rings = 28 subunits), the transcription complex and the spliceosome
Spliceosome
A spliceosome is a complex of snRNA and protein subunits that removes introns from a transcribed pre-mRNA segment. This process is generally referred to as splicing.-Composition:...
. The ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
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.
Determination of quaternary structure
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 determined whether a protein is unfolded or has formed an oligomer.
Prediction of quaternary structure attribute
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 compositionPseudo amino acid composition
Pseudo amino acid composition, or PseAA composition, was originally introduced by Kuo-Chen Chou in 2001 to represent protein samples for improving protein subcellular localization prediction and membrane protein type prediction.- Background :...
(see, e.g., refs.
).
Methods that measure mass of intact complex directly
- sedimentation-equilibrium analytical ultracentrifugation
- electrosprayElectrospray ionizationElectrospray ionization is a technique used in mass spectrometry to produce ions. It is especially useful in producing ions from macromolecules because it overcomes the propensity of these molecules to fragment when ionized...
mass spectrometryMass spectrometryMass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and... - Mass spectrometric immunoassay (MSIA)
Methods that measure the size of the intact complex directly
- static light scatteringRayleigh scatteringRayleigh scattering, named after the British physicist Lord Rayleigh, is the elastic scattering of light or other electromagnetic radiation by particles much smaller than the wavelength of the light. The particles may be individual atoms or molecules. It can occur when light travels through...
- size exclusion chromatographySize exclusion chromatographySize-exclusion chromatography is a chromatographic method in which molecules in solution are separated by their size, and in some cases molecular weight . It is usually applied to large molecules or macromolecular complexes such as proteins and industrial polymers...
(requires calibration) - Dual polarisation interferometryDual Polarisation InterferometryDual polarization interferometry is an analytical technique that can probe molecular scale layers adsorbed to the surface of a waveguide by using the evanescent wave of a laser beam confined to the waveguide...
Methods that measure the size of the intact complex indirectly
- sedimentation-velocity analytical ultracentrifugation (measures the translational diffusion constant)
- dynamic light scatteringDynamic light scatteringthumb|right|350px|Hypothetical Dynamic light scattering of two samples: Larger particles on the top and smaller particle on the bottomDynamic light scattering is a technique in physics that can be used to determine the size distribution profile of small particles in suspension or polymers...
(measures the translational diffusion constant) - pulsed-gradient protein nuclear magnetic resonance (measures the translational diffusion constant)
- fluorescence polarization (measures the rotational diffusion constant)
- dielectric relaxation (measures the rotational diffusion constant)
- Dual polarisation interferometryDual Polarisation InterferometryDual polarization interferometry is an analytical technique that can probe molecular scale layers adsorbed to the surface of a waveguide by using the evanescent wave of a laser beam confined to the waveguide...
(measures the size and the density of the complex)
Methods that measure the mass or volume under unfolding
Denaturation (biochemistry)
Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
conditions (such as
MALDI-TOF
Matrix-assisted laser desorption/ionization
Matrix-assisted laser desorption/ionization is a soft ionization technique used in mass spectrometry, allowing the analysis of biomolecules and large organic molecules , which tend to be fragile and fragment when ionized by more conventional ionization methods...
mass spectrometry
Mass spectrometry
Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and...
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-linking reagents.
Protein-protein interactions
Proteins are capable of forming very tight complexes. For example, ribonuclease inhibitorRibonuclease inhibitor
Ribonuclease inhibitor is a large , acidic , leucine-rich repeat protein that forms extremely tight complexes with certain ribonucleases. It is a major cellular protein, comprising ~0.1% of all cellular protein by weight, and appears to play an important role in regulating the lifetime of RNA.RI...
binds to ribonuclease A
Ribonuclease A
Ribonuclease A is a pancreatic ribonuclease that cleaves single-stranded RNA. Bovine pancreatic RNase A is one of the classic model systems of protein science.-History:...
with a roughly 20 fM dissociation constant
Dissociation constant
In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into...
. 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).
Quaternary or Quartary?
In biology, the non-standard usage "Quaternary structure" is so firmly entrenched that to refer to "Quartary structure" would be incorrect. The correct term should really be "Quartary":- Quartary (from ) is the fourth member of an ordinal numberOrdinal number (linguistics)In linguistics, ordinal numbers are the words representing the rank of a number with respect to some order, in particular order or position . Its use may refer to size, importance, chronology, etc...
word series beginning with (primary, secondary, tertiary) and continuing with (quintary, sextary, ...). - Quaternary (from ) is the fourth member of a distributive number word series beginning with (singular, binary, ternary) and continuing with (quinary, senary, septenary, octonary ... centenary).
See also
- Protein primary structure
- Protein secondary structure
- Protein tertiary structure
- Structural biologyStructural biologyStructural biology is a branch of molecular biology, biochemistry, and biophysics concerned with the molecular structure of biological macromolecules, especially proteins and nucleic acids, how they acquire the structures they have, and how alterations in their structures affect their function...
External links
- The Macromolecular Structure Database (MSD) at the European Bioinformatics InstituteEuropean Bioinformatics InstituteThe European Bioinformatics Institute is a centre for research and services in bioinformatics, and is part of European Molecular Biology Laboratory...
(EBI) — Serves a list of the Probable Quaternary Structure (PQS) for every protein in the Protein Data BankProtein Data BankThe Protein Data Bank is a repository for the 3-D structural data of large biological molecules, such as proteins and nucleic acids....
(PDB). - PQS server — PQS has not been updated since August 2009
- PISA — The Protein Interfaces, Surfaces and Assemblies server at the MSDMSDMSD may refer to:*Macromolecular Structure Database, one of the services provided by the European Bioinformatics Institute*Mahendra Singh Dhoni, Indian cricketer, wicketkeeper batsman*Marine Sanitation Device*Maryland School for the Deaf...
. - 3D complex — Structural classification of protein complexes
- ProteopediaProteopediaProteopedia is a wiki, 3D encyclopedia of proteins and other molecules..The site contains a page for every entry in the Protein Data Bank , as well as pages that are more descriptive of protein structures in general such as acetylcholinesterase, hemoglobin, and the photosystem II with a Jmol view...
— Proteopedia Home Page The collaborative, 3D encyclopedia of proteins and other molecules. - PDBWikiPDBWikiPDBWiki is a wiki that functions as a user-contributed database of protein structure annotations, listing all the protein structures currently available in the Protein Data Bank...
— PDBWiki Home Page - a website for community annotation of PDB structures. - ProtCIDProtCIDThe Protein Common Interface Database is a database of similar protein-protein interfaces in crystal structures of homologous proteins....
— ProtCID -- a database of similar protein-protein interfaces in crystal structures of homologous proteins.