Protein quaternary structure: Difference between revisions

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{{short description|Number and arrangement of multiple folded protein subunits in a multi-subunit complex}}

{{Protein structure}}

{{about|quaternary structure in protein|the article about quaternary structure in nucleic acid|Nucleic acid quaternary structure}}

{{Use dmy dates|date=December 2016}}

{{Protein structure}}

'''Protein quaternary structure'''{{efn|Here ''[[wikt:quaternary|quaternary]]'' means "''fourth-level'' structure", not "''four-way'' interaction". Etymologically ''[[wikt:quartary|quartary]]'' is correct: ''quaternary'' is derived from Latin [[distributive number]]s, and follows ''binary'' and ''ternary''; while ''quartary'' is derived from Latin [[ordinal number]]s, and follows ''secondary'' and ''tertiary''. However, ''quaternary'' is standard in biology.}} is the fourth (and highest) classification level of [[protein structure]]. Protein quaternary structure refers to the structure of proteins which are themselves composed of two or more smaller protein chains (also referred to as subunits). Protein quaternary structure describes the number and arrangement of multiple [[protein folding|folded]] [[protein subunit]]s in a [[Multiprotein complex|multi-subunit complex]]. It includes organizations from simple [[protein dimer|dimers]] to large [[homooligomer]]s and [[multiprotein complex|complexes]] with defined or variable numbers of subunits.<ref>{{cite book| vauthors = Berg JM, Tymoczko JL, Stryer L |title=Biochemistry|date=2002|publisher=W. H. Freeman|___location=New York, NY [u.a.]|isbn=0-7167-3051-0|edition=5. ed., 4. print.|url=https://archive.org/details/biochemistrychap00jere|chapter=Section 3.5Quaternary Structure: Polypeptide Chains Can Assemble Into Multisubunit Structures|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK22550/|url-access=registration}}</ref> In contrast to the first three levels of protein structure, not all proteins will have a quaternary structure since some proteins function as single units. Protein quaternary structure can also refer to [[biomolecular complex]]es of proteins with [[nucleic acid]]s and other [[Cofactor (biochemistry)|cofactors]].

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==Nomenclature==

[[File:1axc tricolor.png|thumb|The quaternary structure of this protein complex would be described as a homo-trimer because it is composed of three identical smaller protein subunits (oralso designated as monomers or protomers).]]

The number of subunits in an [[oligomer]]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.

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* 1 = [[protein subunit|monomer/subunit]]

* 2 = [[protein dimer|dimer]]

* 3 = [[protein trimer|trimer]]

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:<nowiki>*</nowiki>''No known examples''

The smallest unit forming a homo-oligomer, i.e. one protein chain or [[protein subunit|subunit]], is designated as a monomer, subunit or [[Protomer (structural biology)|protomer]]. The latter term was originally devised to specify the smallest unit of hetero-oligomeric proteins, but is also applied to homo-oligomeric proteins in current literature. The subunits usually arrange in [[cyclic symmetry]] to form closed [[point group]] [[symmetries]].

Although complexes higher than octamers are rarely observed for most proteins, there are some important exceptions. [[Capsid|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",. toThis 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 ''C''₄. In this case the four interfaces between the subunits are identical. It may also have point group symmetry 222 or ''D''₂. 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 [[oligomer]]s 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.

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* Surface-induced dissociation mass spectrometry<ref name = "Stiving_2019">{{cite journal | vauthors = Stiving AQ, VanAernum ZL, Busch F, Harvey SR, Sarni SH, Wysocki VH | title = Surface-Induced Dissociation: An Effective Method for Characterization of Protein Quaternary Structure | journal = Analytical Chemistry | volume = 91 | issue = 1 | pages = 190–209 | date = January 2019 | pmid = 30412666 | pmc = 6571034 | doi = 10.1021/acs.analchem.8b05071 | department = review }}</ref>

* Coimmunoprecipation<ref name = "Milligan_2005">{{cite journal | vauthors = Milligan G, Bouvier M | title = Methods to monitor the quaternary structure of G protein-coupled receptors | journal = The FEBS Journal | volume = 272 | issue = 12 | pages = 2914–2925 | date = June 2005 | pmid = 15955052 | doi = 10.1111/j.1742-4658.2005.04731.x | s2cid = 23274563 | department = review }}</ref>

* [[Förster resonance energy transfer|FRET]]<ref name = "Milligan_2005" /><ref name = "Raicu_2013">{{cite journal | vauthors = Raicu V, Singh DR | title = FRET spectrometry: a new tool for the determination of protein quaternary structure in living cells | journal = Biophysical Journal | volume = 105 | issue = 9 | pages = 1937–1945 | date = November 2013 | pmid = 24209838 | pmc = 3824708 | doi = 10.1016/j.bpj.2013.09.015 | bibcode = 2013BpJ...105.1937R | department = primary }}</ref>

* Nuclear Magnetic Resonance (NMR)<ref name="Prischi_2016">{{cite journalbook | vauthors = Prischi F, Pastore A | title = Advanced Technologies for Protein Complex Production and Characterization | chapter = Application of Nuclear Magnetic Resonance and Hybrid Methods to Structure Determination of Complex Systems | journalseries = Advances in Experimental Medicine and Biology | volume = 896 | issue = | pages = 351–368 | date = 2016 | pmid = 27165336 | doi = 10.1007/978-3-319-27216-0_22 | isbn = 978-3-319-27214-6 | department = review }}</ref><ref name="Wells_2018">{{cite book | vauthors = Wells JN, Marsh JA | title = Protein Complex Assembly | chapter = Experimental Characterization of Protein Complex Structure, Dynamics, and Assembly | series = Methods in Molecular Biology | volume = 1764 | pages = 3–27 | date = 2018 | pmid = 29605905 | doi = 10.1007/978-1-4939-7759-8_1 | isbn = 978-1-4939-7758-1 | quote = Section 4: Nuclear Magnetic Resonance Spectroscopy | department = review }}</ref>

===Direct mass measurement of intact complexes===

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== 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.<ref>{{cite journal | vauthors = Heldin CH | title = Dimerization of cell surface receptors in signal transduction | journal = Cell | volume = 80 | issue = 2 | pages = 213–223 | date = January 1995 | pmid = 7834741 | doi = 10.1016/0092-8674(95)90404-2 | s2cid = 18925209 | doi-access = free }}</ref>

==Protein–protein interactions==

{{main|Protein–protein interaction}}

Proteins are capable of forming very tight but also only transient 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___domain]]s) or proline-rich segments ([[SH3 domains___domain]]s). Protein-proteinProtein–protein interactions can be engineered to favor certain oligomerization states.<ref>{{cite journal | vauthors = Ardejani MS, Chok XL, Foo CJ, Orner BP | title = Complete shift of ferritin oligomerization toward nanocage assembly via engineered protein-protein interactions | journal = Chemical Communications | volume = 49 | issue = 34 | pages = 3528–3530 | date = May 2013 | pmid = 23511498 | doi = 10.1039/C3CC40886H }}</ref>

==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.<ref>{{cite journal | vauthors = Crick FH, Orgel LE | title = The theory of inter-allelic complementation | journal = Journal of Molecular Biology | volume = 8 | pages = 161–165 | date = January 1964 | pmid = 14149958 | doi = 10.1016/s0022-2836(64)80156-x }}</ref> When a multimer is formed from polypeptides produced by two different [[mutant]] [[allele]]s 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 [[complementation (genetics)#Intragenic complementation|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 [[Escherichia virus T4|bacteriophage T4]],<ref>{{cite journal | vauthors = Bernstein H, Edgar RS, Denhardt GH | title = Intragenic complementation among temperature sensitive mutants of bacteriophage T4D | journal = Genetics | volume = 51 | issue = 6 | pages = 987–1002 | date = June 1965 | pmid = 14337770 | pmc = 1210828 | doi = 10.1093/genetics/51.6.987 }}</ref> an RNA virus,<ref>{{cite journal | vauthors = Smallwood S, Cevik B, Moyer SA | title = Intragenic complementation and oligomerization of the L subunit of the sendai virus RNA polymerase | journal = Virology | volume = 304 | issue = 2 | pages = 235–245 | date = December 2002 | pmid = 12504565 | doi = 10.1006/viro.2002.1720 | doi-access = free }}</ref> and humans.<ref>{{cite journal | vauthors = Rodríguez-Pombo P, Pérez-Cerdá C, Pérez B, Desviat LR, Sánchez-Pulido L, Ugarte M | title = Towards a model to explain the intragenic complementation in the heteromultimeric protein propionyl-CoA carboxylase | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1740 | issue = 3 | pages = 489–498 | date = June 2005 | pmid = 15949719 | doi = 10.1016/j.bbadis.2004.10.009 | doi-access = free }}</ref> The intermolecular forces likely responsible for self-recognition and multimer formation were discussed by Jehle.<ref>{{cite journal | vauthors = Jehle H | title = Intermolecular forces and biological specificity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 50 | issue = 3 | pages = 516–524 | date = September 1963 | pmid = 16578546 | pmc = 221211 | doi = 10.1073/pnas.50.3.516 | bibcode = 1963PNAS...50..516J | doi-access = free }}</ref>

==Assembly==

Direct interaction of two nascent proteins emerging from nearby [[ribosome]]s appears to be a general mechanism for oligomer formation.<ref name="Bertolini_2021">{{cite journal | vauthors = Bertolini M, Fenzl K, Kats I, Wruck F, Tippmann F, Schmitt J, Auburger JJ, Tans S, Bukau B, Kramer G | display-authors = 6 | title = Interactions between nascent proteins translated by adjacent ribosomes drive homomer assembly | journal = Science | volume = 371 | issue = 6524 | pages = 57–64 | date = January 2021 | pmid = 33384371 | doi = 10.1126/science.abc7151 | pmc = 7613021 | bibcode = 2021Sci...371...57B | s2cid = 229935047 | url = https://ir.amolf.nl/pub/10361 | department = primary }}</ref> Hundreds of protein oligomers were identified that assemble in human cells by such an interaction.<ref name="Bertolini_2021" /> 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 ==