Editing Protein complex

{{short description|Type of stable macromolecular complex}}
[[Image:Kinesin_walking.gif|thumb|300px| [[Kinesin]] is a protein functioning as a molecular [[biological machine]]. It uses [[protein dynamics#Global flexibility: multiple domains|protein domain dynamics]] on [[Nanoscopic scale|nanoscale]]s]]

A '''protein complex''' or '''multiprotein complex''' is a group of two or more associated [[polypeptide chain]]s. Protein complexes are distinct from [[multidomain enzymes]], in which multiple [[active site|catalytic domains]] are found in a single polypeptide chain.<ref>{{Cite book  |vauthors=Price NC, Stevens L | title = Fundamentals of Enzymology: The Cell and Molecular Biology of Catalytic Proteins | date = 1999 | publisher = Oxford University Press | location = Oxford| isbn = 0-19-850229-X | edition = 3rd }}</ref>

Protein complexes are a form of [[protein quaternary structure|quaternary structure.]] [[Protein]]s in a protein complex are linked by [[non-covalent interactions|non-covalent]] [[protein–protein interaction]]s. These complexes are a cornerstone of many (if not most) biological processes. The cell is seen to be composed of modular supramolecular complexes, each of which performs an independent, discrete biological function.<ref name="pmid10591225">{{cite journal |vauthors=Hartwell LH, Hopfield JJ, Leibler S, Murray AW | title = From molecular to modular cell biology | journal = Nature | volume = 402 | issue = 6761 Suppl | pages = C47–52 |date=December 1999 | pmid = 10591225 | doi = 10.1038/35011540 | doi-access = free }}</ref>

Through proximity, the speed and selectivity of binding interactions between [[Enzyme|enzymatic]] complex and substrates can be vastly improved, leading to higher cellular efficiency. Many of the techniques used to enter cells and isolate proteins are inherently disruptive to such large complexes, complicating the task of determining the components of a complex.

Examples of protein complexes include the [[proteasome]] for molecular degradation and most [[RNA polymerase]]s. In stable complexes, large hydrophobic interfaces between proteins typically bury surface areas larger than 2500 square [[ångström|Å]]s.<ref name="pmid16524839">{{cite journal |vauthors=Pereira-Leal JB, Levy ED, Teichmann SA | title = The origins and evolution of functional modules: lessons from protein complexes | journal = Philos. Trans. R. Soc. Lond. B Biol. Sci. | volume = 361 | issue = 1467 | pages = 507–17 |date=March 2006 | pmid = 16524839 | pmc = 1609335 | doi = 10.1098/rstb.2005.1807 }}</ref>

== Function ==
[[Image:Barnase-barstar-1brs.png|thumb|right|250px|The ''[[Bacillus amyloliquefaciens]]'' [[ribonuclease]] [[barnase]] (colored) and its [[enzyme inhibitor|inhibitor]] (blue) in a complex]]
Protein complex formation can activate or inhibit one or more of the complex members and in this way, protein complex formation can be similar to [[phosphorylation]]. Individual proteins can participate in a variety of protein complexes. Different complexes perform different functions, and the same complex can perform multiple functions depending on various factors. Factors include:

* Cell compartment location
* Cell cycle stage
* Cell nutritional status{{citation needed|date=April 2019}}

Many protein complexes are well understood, particularly in the [[model organism]] ''[[Saccharomyces cerevisiae]]'' (yeast). For this relatively simple organism, the study of protein complexes is now [[genome]] wide and the elucidation of most of its protein complexes is ongoing.{{citation needed|date=June 2019}} In 2021, researchers used [[deep learning]] software [[Rosetta@home#RoseTTAFold|RoseTTAFold]] along with [[AlphaFold]] to solve the structures of 712 [[eukaryote]] complexes. They compared 6000 yeast proteins to those from 2026 other fungi and 4325 other eukaryotes.<ref>{{Cite web|title=AI cracks the code of protein complexes—providing a road map for new drug targets|url=https://www.science.org/content/article/ai-cracks-code-protein-complexes-providing-road-map-new-drug-targets|access-date=2021-11-14|website=www.science.org|language=en}}</ref>

==Types of protein complexes==

=== Obligate vs non-obligate protein complex ===
If a protein can form a stable well-folded structure on its own (without any other associated protein) ''in vivo'', then the complexes formed by such proteins are termed "non-obligate protein complexes". However, some proteins can't be found to create a stable well-folded structure alone, but can be found as a part of a protein complex which stabilizes the constituent proteins. Such protein complexes are called "obligate protein complexes".<ref name = "Amoutzias_2010">{{ cite book |vauthors=Amoutzias G, Van de Peer Y | year = 2010 | chapter = Single-Gene and Whole-Genome Duplications and the Evolution of Protein–Protein Interaction Networks. Evolutionary genomics and systems biology | pages = 413–429 | doi = 10.1002/9780470570418.ch19 | title=Evolutionary Genomics|editor-first=Gustavo|editor-last=Caetano-Anolles}}</ref>

=== Transient vs permanent/stable protein complex ===
Transient protein complexes form and break down transiently ''in vivo'', whereas permanent complexes have a relatively long half-life. Typically, the obligate interactions (protein–protein interactions in an obligate complex) are permanent, whereas non-obligate interactions have been found to be either permanent or transient.<ref name = "Amoutzias_2010"/> Note that there is no clear distinction between obligate and non-obligate interaction, rather there exist a continuum between them which depends on various conditions e.g. pH, protein concentration etc.<ref name="pmid12853464">{{cite journal |vauthors=Nooren IM, Thornton JM | title = Diversity of protein interactions | journal = EMBO J. | volume = 22 | issue = 14 | pages = 3486–92 |date=July 2003 | pmid = 12853464 | pmc = 165629 | doi = 10.1093/emboj/cdg359 }}</ref> However, there are important distinctions between the properties of transient and permanent/stable interactions: stable interactions are highly conserved but transient interactions are far less conserved, interacting proteins on the two sides of a stable interaction have more tendency of being co-expressed than those of a transient interaction (in fact, co-expression probability between two transiently interacting proteins is not higher than two random proteins), and transient interactions are much less co-localized than stable interactions.<ref name="pmid17535438">{{cite journal |vauthors=Brown KR, Jurisica I | title = Unequal evolutionary conservation of human protein interactions in interologous networks | journal = Genome Biol. | volume = 8 | issue = 5 | pages = R95 | year = 2007 | pmid = 17535438 | pmc = 1929159 | doi = 10.1186/gb-2007-8-5-r95 | doi-access = free }}</ref> Though, transient by nature, transient interactions are very important for cell biology: the human interactome is enriched in such interactions, these interactions are the dominating players of gene regulation and signal transduction, and proteins with ''intrinsically disordered regions'' (IDR: regions in protein that show dynamic inter-converting structures in the native state) are found to be enriched in transient regulatory and signaling interactions.<ref name = "Amoutzias_2010"/>

=== Fuzzy complex ===
[[Fuzzy complex|Fuzzy protein complexes]] have more than one structural form or dynamic structural disorder in the bound state.<ref name="pmid18054235">{{cite journal |vauthors=Tompa P, Fuxreiter M | title = Fuzzy complexes: polymorphism and structural disorder in protein–protein interactions | journal = Trends Biochem. Sci. | volume = 33 | issue = 1 | pages = 2–8 |date=January 2008 | pmid = 18054235 | doi = 10.1016/j.tibs.2007.10.003 }}</ref> This means that proteins may not fold completely in either transient or permanent complexes. Consequently, specific complexes can have ambiguous interactions, which vary according to the environmental signals. Hence different ensembles of structures result in different (even opposite) biological functions.<ref name="pmid21927770">{{cite journal | author = Fuxreiter M | title = Fuzziness: linking regulation to protein dynamics | journal = Mol Biosyst | volume = 8 | issue = 1 | pages = 168–77 |date=January 2012 | pmid = 21927770 | doi = 10.1039/c1mb05234a }}</ref> Post-translational modifications, protein interactions or alternative splicing modulate the [[conformational ensembles]] of fuzzy complexes, to fine-tune affinity or specificity of interactions. These mechanisms are often used for regulation within the [[eukaryotic transcription]] machinery.<ref name="pmid21620710">{{cite journal |vauthors=Fuxreiter M, Simon I, Bondos S | title = Dynamic protein–DNA recognition: beyond what can be seen | journal = Trends Biochem. Sci. | volume = 36 | issue = 8 | pages = 415–23 |date=August 2011 | pmid = 21620710 | doi = 10.1016/j.tibs.2011.04.006 }}</ref>

== Essential proteins in protein complexes ==

[[Image:Essential proteins in yeast complexes.png|thumb|right|250px|Essential proteins in yeast complexes occur much less randomly than expected by chance. Modified after Ryan et al. 2013<ref name="Ryan2013"/>]]

Although some early studies<ref name="Jeong2001">{{Cite journal
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| year = 2001
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}}</ref> suggested a strong correlation between essentiality and protein interaction degree (the "centrality-lethality" rule) subsequent analyses have shown that this correlation is weak for binary or transient interactions (e.g., [[Yeast two hybrid|yeast two-hybrid]]).<ref name="Yu2008">{{Cite journal
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| title = Why do hubs in the yeast protein interaction network tend to be essential: Reexamining the connection between the network topology and essentiality
| journal = PLOS Computational Biology
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}}</ref> However, the correlation is robust for networks of stable co-complex interactions. In fact, a disproportionate number of [[essential genes]] belong to protein complexes.<ref name="Hart2007">{{Cite journal
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| year = 2007
| last1 = Hart
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| title = A high-accuracy consensus map of yeast protein complexes reveals modular nature of gene essentiality
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}}</ref> This led to the conclusion that essentiality is a property of molecular machines (i.e. complexes) rather than individual components.<ref name="Hart2007"/> Wang et al. (2009) noted that larger protein complexes are more likely to be essential, explaining why essential genes are more likely to have high co-complex interaction degree.<ref name="Wang2009">{{Cite journal
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}}</ref> Ryan et al. (2013) referred to the observation that entire complexes appear essential as "'''modular essentiality'''".<ref name="Ryan2013">{{Cite journal
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}}</ref> These authors also showed that complexes tend to be composed of either essential or non-essential proteins rather than showing a random distribution (see Figure). However, this not an all or nothing phenomenon: only about 26% (105/401) of yeast complexes consist of solely essential or solely nonessential subunits.<ref name="Ryan2013" />

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==Homomultimeric and heteromultimeric proteins==
The subunits of a multimeric protein may be identical as in a homomultimeric (homooligomeric) protein or different as in a heteromultimeric protein. Many soluble and membrane proteins form homomultimeric complexes in a cell, majority of proteins in the [[Protein Data Bank]] are homomultimeric.<ref name="pmid21572178">{{cite journal |vauthors=Hashimoto K, Nishi H, Bryant S, Panchenko AR | title = Caught in self-interaction: evolutionary and functional mechanisms of protein homooligomerization | journal = Phys Biol | volume = 8 | issue = 3 | pages = 035007 |date=June 2011 | pmid = 21572178 | pmc = 3148176 | doi = 10.1088/1478-3975/8/3/035007 | bibcode = 2011PhBio...8c5007H }}</ref> Homooligomers are responsible for the diversity and specificity of many pathways, may mediate and regulate gene expression, activity of enzymes, ion channels, receptors, and cell adhesion processes.

The [[voltage-gated potassium channels]] in the plasma membrane of a neuron are heteromultimeric proteins composed of four of forty known alpha subunits. Subunits must be of the same subfamily to form the multimeric protein channel. The tertiary structure of the channel allows ions to flow through the hydrophobic plasma membrane. [[Connexon]]s are an example of a homomultimeric protein composed of six identical [[connexin]]s. A cluster of connexons forms the gap-junction in two neurons that transmit signals through an [[electrical synapse]].

===Intragenic complementation===

When multiple copies of a polypeptide encoded by a [[gene]] form a complex, this protein structure is referred to as a multimer. 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 has been demonstrated 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 |last1=Bernstein |first1=H |last2=Edgar |first2=RS |last3=Denhardt |first3=GH |title=Intragenic Complementation among Temperature Sensitive Mutants of Bacteriophage T4D |journal=Genetics |date=June 1965 |volume=51 |issue=6 |pages=987–1002 |doi=10.1093/genetics/51.6.987 |pmid=14337770 |pmc=1210828}}</ref> an RNA virus<ref>Smallwood S, Cevik B, Moyer SA. Intragenic complementation and oligomerization of the L subunit of the sendai virus RNA polymerase. Virology. 2002;304(2):235-245. {{doi|10.1006/viro.2002.1720}}</ref> and humans.<ref>Rodríguez-Pombo P, Pérez-Cerdá C, Pérez B, Desviat LR, Sánchez-Pulido L, Ugarte M. Towards a model to explain the intragenic complementation in the heteromultimeric protein propionyl-CoA carboxylase. Biochim Biophys Acta. 2005;1740(3):489-498. {{doi|10.1016/j.bbadis.2004.10.009}}</ref> In such studies, numerous [[mutation]]s defective in the same gene were often isolated and mapped in a linear order on the basis of [[genetic recombination|recombination]] frequencies to form a [[gene mapping|genetic map]] of the gene. Separately, the mutants were tested in pairwise combinations to measure complementation. An analysis of the results from such studies led to the conclusion that intragenic complementation, in general, arises from the interaction of differently defective polypeptide monomers to form a multimer.<ref>Crick FH, Orgel LE.  The theory of inter-allelic complementation. J Mol Biol. 1964 Jan;8:161-5. {{doi|10.1016/s0022-2836(64)80156-x}}. PMID 14149958</ref> Genes that encode multimer-forming polypeptides appear to be common. One interpretation of the data is that polypeptide monomers are often aligned in the multimer in such a way that mutant polypeptides defective at nearby sites in the genetic map tend to form a mixed multimer that functions poorly, whereas mutant polypeptides defective at distant sites tend to form a mixed multimer that functions more effectively. The intermolecular forces likely responsible for self-recognition and multimer formation were discussed by Jehle.<ref>Jehle H. Intermolecular forces and biological specificity.  Proc Natl Acad Sci U S A. 1963;50(3):516-524. {{doi|10.1073/pnas.50.3.516}}</ref>

== Structure determination ==

The [[molecular structure]] of protein complexes can be determined by experimental techniques such as [[X-ray crystallography]], [[Single particle analysis]] or [[nuclear magnetic resonance]]. Increasingly the theoretical option of [[protein–protein docking]] is also becoming available. One method that is commonly used for identifying the meomplexes{{Clarify|What is this term|date=May 2017}} is [[immunoprecipitation]]. Recently, Raicu and coworkers developed a method to determine the quaternary structure of protein complexes in living cells. This method is based on the determination of pixel-level [[Förster resonance energy transfer]] (FRET) efficiency in conjunction with spectrally resolved [[two-photon microscope]]. The distribution of FRET efficiencies are simulated against different models to get the geometry and stoichiometry of the complexes.<ref>{{ cite journal | author = Raicu V, Stoneman MR, Fung R, Melnichuk M, Jansma DB, Pisterzi LF, Rath S, Fox, M, Wells, JW, Saldin DK | year = 2008 | title = Determination of supramolecular structure and spatial distribution of protein complexes in living cells. | journal = Nature Photonics | volume =  3 | issue = 2 | pages = 107–113 | doi = 10.1038/nphoton.2008.291 }}</ref>

==Assembly==

Proper assembly of multiprotein complexes is important, since misassembly can lead to disastrous consequences.<ref>{{cite journal|last1=Dobson|first1=Christopher M|title=Protein folding and misfolding|journal=Nature|date=December 2003|volume=426|issue=6968|pages=884–90|doi=10.1038/nature02261|pmid=14685248|bibcode=2003Natur.426..884D|s2cid=1036192}}</ref> In order to study pathway assembly, researchers look at intermediate steps in the pathway. One such technique that allows one to do that is [[electrospray mass spectrometry]], which can identify different intermediate states simultaneously. This has led to the discovery that most complexes follow an ordered assembly pathway.<ref name = "pmid23582331">{{cite journal |vauthors=Marsh JA, Hernández H, Hall Z, Ahnert SE, Perica T, Robinson CV, Teichmann SA | title = Protein complexes are under evolutionary selection to assemble via ordered pathways | journal = Cell | volume = 153 | issue = 2 | pages = 461–470 | date = Apr 2013 | pmid = 23582331 | doi = 10.1016/j.cell.2013.02.044 | pmc=4009401}}</ref> In the cases where disordered assembly is possible, the change from an ordered to a disordered state leads to a transition from function to dysfunction of the complex, since disordered assembly leads to aggregation.<ref>{{cite journal|last1=Sudha|first1=Govindarajan|last2=Nussinov|first2=Ruth|last3=Srinivasan|first3=Narayanaswamy|title=An overview of recent advances in structural bioinformatics of protein–protein interactions and a guide to their principles|journal=Progress in Biophysics and Molecular Biology|year=2014|volume=116|issue=2–3|pages=141–50|doi=10.1016/j.pbiomolbio.2014.07.004|pmid=25077409}}</ref>

The structure of proteins play a role in how the multiprotein complex assembles. The interfaces between proteins can be used to predict assembly pathways.<ref name = "pmid23582331"/> The intrinsic flexibility of proteins also plays a role: more flexible proteins allow for a greater surface area available for interaction.<ref>{{cite journal|last1=Marsh|first1=Joseph|last2=Teichmann|first2=Sarah A|title=Protein flexibility facilitates quaternary structure assembly and evolution|journal=PLOS Biology|date=May 2014|volume=12|issue=5|doi=10.1371/journal.pbio.1001870|pmid=24866000|pages=e1001870|pmc=4035275 |doi-access=free }}</ref>

While assembly is a different process from disassembly, the two are reversible in both homomeric and heteromeric complexes. Thus, the overall process can be referred to as (dis)assembly.

===Evolutionary significance of multiprotein complex assembly===
In homomultimeric complexes, the [[homomeric]] proteins assemble in a way that mimics evolution. That is, an intermediate in the assembly process is present in the complex's evolutionary history.<ref>{{cite journal|last1=Levy|first1=Emmanuel D|last2=Boeri Erba|first2=Elisabetta|last3=Robinson|first3=Carol V|last4=Teichmann|first4=Sarah A|title=Assembly reflects evolution of protein complexes|journal=Nature|date=July 2008|volume=453|issue=7199|pages=1262–5|doi=10.1038/nature06942|pmid=18563089|pmc=2658002|bibcode=2008Natur.453.1262L}}</ref>
The opposite phenomenon is observed in heteromultimeric complexes, where gene fusion occurs in a manner that preserves the original assembly pathway.<ref name = "pmid23582331"/>

== See also ==
*[[Heterotetramer]]
*[[Biomolecular complex]]
*[[Protein subunit]]

== References ==
{{reflist|35em}}

== External links ==
* {{MeshName|Multiprotein+Complexes}}

{{Protein topics}}
{{Multienzyme complexes}}

[[Category:Protein complexes| ]]