Protein quaternary structure
Protein quaternary structure
Description and examples
Many proteins are actually assemblies of multiple
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.
Nomenclature
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.
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- *No known examples
The smallest unit forming a homo-oligomer, i.e. one protein chain or
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". This may suggest that the complex might dissociate into smaller sub-complexes before dissociating into monomers. This usually implies that the complex consists of different oligomerisation interfaces. For example, a tetrameric protein may have one four-fold rotation axis, i.e. point group symmetry 4 or C4. In this case the four interfaces between the subunits are identical. It may also have point group symmetry 222 or D2. This tetramer has different interfaces and the tetramer can dissociate into two identical homodimers. Tetramers of 222 symmetry are "dimer of dimers". Hexamers of 32 point group symmetry are "trimer of dimers" or "dimer of trimers". Thus, the nomenclature "dimer of dimers" is used to specify the point group symmetry or arrangement of the oligomer, independent of information relating to its dissociation properties.
Another distinction often made when referring to oligomers is whether they are homomeric or heteromeric, referring to whether the smaller protein subunits that come together to make the protein complex are the same (homomeric) or different (heteromeric) from each other. For example, two identical protein monomers would come together to form a homo-dimer, whereas two different protein monomers would create a hetero-dimer.
Structure Determination
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.
Common techniques used to study protein quaternary structure
- Ultracentrifugation
- Surface-induced dissociation mass spectrometry[3]
- Coimmunoprecipation[4]
- FRET[4][5]
- Nuclear Magnetic Resonance (NMR)[6][7]
Direct mass measurement of intact complexes
- Sedimentation-equilibrium analytical ultracentrifugation
- Electrospray mass spectrometry
- Mass Spectrometric ImmunoassayMSIA
Direct size measurement of intact complexes
- Static light scattering
- Size exclusion chromatography(requires calibration)
- Dual polarisation interferometry
Indirect size measurement of intact complexes
- Sedimentation-velocity diffusion constant)
- diffusion constant)
- Pulsed-gradient diffusion constant)
- diffusion constant)
- diffusion constant)
- Dual polarisation interferometry(measures the size and the density of the complex)
Methods that measure the mass or volume under unfolding conditions (such as
Structure Prediction
Some bioinformatics methods have been developed for predicting the quaternary structural attributes of proteins based on their sequence information by using various modes of pseudo amino acid composition.[2][8][9]
Protein folding prediction programs used to predict protein tertiary structure have also been expanding to better predict protein quaternary structure. One such development is AlphaFold-Multimer[10] built upon the AlphaFold model for predicting protein tertiary structure.
Role in Cell Signaling
Protein quaternary structure also plays an important role in certain cell signaling pathways. The G-protein coupled receptor pathway involves a heterotrimeric protein known as a G-protein. G-proteins contain three distinct subunits known as the G-alpha, G-beta, and G-gamma subunits. When the G-protein is activated, it binds to the G-protein coupled receptor protein and the cell signaling pathway is initiated. Another example is the receptor tyrosine kinase (RTK) pathway, which is initiated by the dimerization of two receptor tyrosine kinase monomers. When the dimer is formed, the two kinases can phosphorylate each other and initiate a cell signaling pathway.[11]
Protein–protein interactions
Proteins are capable of forming very tight but also only transient complexes. For example,
Intragenic complementation
When multiple copies of a polypeptide encoded by a gene form a quaternary complex, this protein structure is referred to as a multimer.[13] 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,[14] an RNA virus,[15] and humans.[16] The intermolecular forces likely responsible for self-recognition and multimer formation were discussed by Jehle.[17]
Assembly
Direct interaction of two nascent proteins emerging from nearby ribosomes appears to be a general mechanism for oligomer formation.[18] Hundreds of protein oligomers were identified that assemble in human cells by such an interaction.[18] 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 also
- Structural biology
- Nucleic acid quaternary structure
- Multiprotein complex
- Biomolecular complex
- Oligomers
Notes
- 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.
References
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Section 4: Nuclear Magnetic Resonance Spectroscopy
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- .
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- PMID 23511498.
- PMID 14149958.
- PMID 14337770.
- PMID 12504565.
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- ^ S2CID 229935047.
External links
- The Macromolecular Structure Database (MSD) at the European Bioinformatics Institute (EBI) – Serves a list of the Probable Quaternary Structure (PQS) for every protein in the Protein Data Bank (PDB).
- PQS server – PQS has not been updated since August 2009
- PISA – The Protein Interfaces, Surfaces and Assemblies server at the MSD.
- EPPIC – Evolutionary Protein–Protein Interface Classification: evolutionary assessment of interfaces in crystal structures
- 3D complex – Structural classification of protein complexes
- Proteopedia – Proteopedia Home Page The collaborative, 3D encyclopedia of proteins and other molecules.
- PDBWiki – PDBWiki Home Page – a website for community annotation of PDB structures.
- ProtCID – ProtCID—a database of similar protein–protein interfaces in crystal structures of homologous proteins.