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Protein complex

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A protein complex or multiprotein complex is a group of two or more associated <a href="Polypeptide_chain" class="mw-redirect" title="Polypeptide chain">polypeptide chains</a>. Protein complexes are distinct from multidomain enzymes, in which multiple <a href="Active_site" title="Active site">catalytic domains</a> are found in a single polypeptide chain.<a href="#cite_note-1">[1]</a>

Protein complexes are a form of <a href="Protein_quaternary_structure" title="Protein quaternary structure">quaternary structure.</a> <a href="Protein" title="Protein">Proteins</a> in a protein complex are linked by <a href="Non-covalent_interactions" class="mw-redirect" title="Non-covalent interactions">non-covalent</a> <a href="Protein%E2%80%93protein_interaction" title="Protein–protein interaction">protein–protein interactions</a>. 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.<a href="#cite_note-pmid10591225-2">[2]</a>

Through proximity, the speed and selectivity of binding interactions between <a href="Enzyme" title="Enzyme">enzymatic</a> 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 <a href="Proteasome" title="Proteasome">proteasome</a> for molecular degradation and most <a href="RNA_polymerase" title="RNA polymerase">RNA polymerases</a>. In stable complexes, large hydrophobic interfaces between proteins typically bury surface areas larger than 2500 square <a href="%C3%85ngstr%C3%B6m" class="mw-redirect" title="Ångström">Ås</a>.<a href="#cite_note-pmid16524839-3">[3]</a>

<div class="mw-heading mw-heading2"><h2 id="Function">Function</h2></div>

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 <a href="Phosphorylation" title="Phosphorylation">phosphorylation</a>. 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:

<ul><li>Cell compartment location</li>

<li>Cell cycle stage</li>

<li>Cell nutritional status</li></ul>

Many protein complexes are well understood, particularly in the <a href="Model_organism" title="Model organism">model organism</a> <a href="Saccharomyces_cerevisiae" title="Saccharomyces cerevisiae">Saccharomyces cerevisiae</a> (yeast). For this relatively simple organism, the study of protein complexes is now <a href="Genome" title="Genome">genome</a> wide and the elucidation of most of its protein complexes is ongoing. In 2021, researchers used <a href="Deep_learning" title="Deep learning">deep learning</a> software <a href="Rosetta%40home#RoseTTAFold" title="Rosetta@home">RoseTTAFold</a> along with <a href="AlphaFold" title="AlphaFold">AlphaFold</a> to solve the structures of 712 <a href="Eukaryote" title="Eukaryote">eukaryote</a> complexes. They compared 6000 yeast proteins to those from 2026 other fungi and 4325 other eukaryotes.<a href="#cite_note-4">[4]</a>

<div class="mw-heading mw-heading2"><h2 id="Types_of_protein_complexes">Types of protein complexes</h2></div>

<div class="mw-heading mw-heading3"><h3 id="Obligate_vs_non-obligate_protein_complex">Obligate vs non-obligate protein complex</h3></div>

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".<a href="#cite_note-Amoutzias_2010-5">[5]</a>

<div class="mw-heading mw-heading3"><h3 id="Transient_vs_permanent/stable_protein_complex">Transient vs permanent/stable protein complex</h3></div>

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.<a href="#cite_note-Amoutzias_2010-5">[5]</a> 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.<a href="#cite_note-pmid12853464-6">[6]</a> 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.<a href="#cite_note-pmid17535438-7">[7]</a> 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.<a href="#cite_note-Amoutzias_2010-5">[5]</a>

<div class="mw-heading mw-heading3"><h3 id="Fuzzy_complex">Fuzzy complex</h3></div>

<a href="Fuzzy_complex" title="Fuzzy complex">Fuzzy protein complexes</a> have more than one structural form or dynamic structural disorder in the bound state.<a href="#cite_note-pmid18054235-8">[8]</a> 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.<a href="#cite_note-pmid21927770-9">[9]</a> Post-translational modifications, protein interactions or alternative splicing modulate the <a href="Conformational_ensembles" title="Conformational ensembles">conformational ensembles</a> of fuzzy complexes, to fine-tune affinity or specificity of interactions. These mechanisms are often used for regulation within the <a href="Eukaryotic_transcription" title="Eukaryotic transcription">eukaryotic transcription</a> machinery.<a href="#cite_note-pmid21620710-10">[10]</a>

<div class="mw-heading mw-heading2"><h2 id="Essential_proteins_in_protein_complexes">Essential proteins in protein complexes</h2></div>

Although some early studies<a href="#cite_note-Jeong2001-12">[12]</a> 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., <a href="Yeast_two_hybrid" class="mw-redirect" title="Yeast two hybrid">yeast two-hybrid</a>).<a href="#cite_note-Yu2008-13">[13]</a><a href="#cite_note-Zotenko2008-14">[14]</a> However, the correlation is robust for networks of stable co-complex interactions. In fact, a disproportionate number of <a href="Essential_genes" class="mw-redirect" title="Essential genes">essential genes</a> belong to protein complexes.<a href="#cite_note-Hart2007-15">[15]</a> This led to the conclusion that essentiality is a property of molecular machines (i.e. complexes) rather than individual components.<a href="#cite_note-Hart2007-15">[15]</a> 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.<a href="#cite_note-Wang2009-16">[16]</a> Ryan et al. (2013) referred to the observation that entire complexes appear essential as "modular essentiality".<a href="#cite_note-Ryan2013-11">[11]</a> 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.<a href="#cite_note-Ryan2013-11">[11]</a>

In humans, genes whose protein products belong to the same complex are more likely to result in the same disease phenotype.<a href="#cite_note-Fraser2007-17">[17]</a><a href="#cite_note-Lage2007-18">[18]</a><a href="#cite_note-Oti2007-19">[19]</a>

<div class="mw-heading mw-heading2"><h2 id="Homomultimeric_and_heteromultimeric_proteins">Homomultimeric and heteromultimeric proteins</h2></div>

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 <a href="Protein_Data_Bank" title="Protein Data Bank">Protein Data Bank</a> are homomultimeric.<a href="#cite_note-pmid21572178-20">[20]</a> 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 <a href="Voltage-gated_potassium_channels" class="mw-redirect" title="Voltage-gated potassium channels">voltage-gated potassium channels</a> 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. <a href="Connexon" title="Connexon">Connexons</a> are an example of a homomultimeric protein composed of six identical <a href="Connexin" title="Connexin">connexins</a>. A cluster of connexons forms the gap-junction in two neurons that transmit signals through an <a href="Electrical_synapse" title="Electrical synapse">electrical synapse</a>.

<div class="mw-heading mw-heading3"><h3 id="Intragenic_complementation">Intragenic complementation</h3></div>

When multiple copies of a polypeptide encoded by a <a href="Gene" title="Gene">gene</a> form a complex, this protein structure is referred to as a multimer. When a multimer is formed from polypeptides produced by two different <a href="Mutant" title="Mutant">mutant</a> <a href="Allele" title="Allele">alleles</a> 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 <a href="Complementation_(genetics)#Intragenic_complementation" title="Complementation (genetics)">intragenic complementation</a> (also called inter-allelic complementation). Intragenic complementation has been demonstrated in many different genes in a variety of organisms including the fungi <a href="Neurospora_crassa" title="Neurospora crassa">Neurospora crassa</a>, <a href="Saccharomyces_cerevisiae" title="Saccharomyces cerevisiae">Saccharomyces cerevisiae</a> and <a href="Schizosaccharomyces_pombe" title="Schizosaccharomyces pombe">Schizosaccharomyces pombe</a>; the bacterium <a href="Salmonella" title="Salmonella">Salmonella</a> typhimurium; the virus <a href="Escherichia_virus_T4" title="Escherichia virus T4">bacteriophage T4</a>,<a href="#cite_note-21">[21]</a> an RNA virus<a href="#cite_note-22">[22]</a> and humans.<a href="#cite_note-23">[23]</a> In such studies, numerous <a href="Mutation" title="Mutation">mutations</a> defective in the same gene were often isolated and mapped in a linear order on the basis of <a href="Genetic_recombination" title="Genetic recombination">recombination</a> frequencies to form a <a href="Gene_mapping" title="Gene mapping">genetic map</a> 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.<a href="#cite_note-24">[24]</a> 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.<a href="#cite_note-25">[25]</a>

<div class="mw-heading mw-heading2"><h2 id="Structure_determination">Structure determination</h2></div>

The <a href="Molecular_structure" class="mw-redirect" title="Molecular structure">molecular structure</a> of protein complexes can be determined by experimental techniques such as <a href="X-ray_crystallography" title="X-ray crystallography">X-ray crystallography</a>, <a href="Single_particle_analysis" title="Single particle analysis">Single particle analysis</a> or <a href="Nuclear_magnetic_resonance" title="Nuclear magnetic resonance">nuclear magnetic resonance</a>. Increasingly the theoretical option of <a href="Protein%E2%80%93protein_docking" class="mw-redirect" title="Protein–protein docking">protein–protein docking</a> is also becoming available. One method that is commonly used for identifying the meomplexes is <a href="Immunoprecipitation" title="Immunoprecipitation">immunoprecipitation</a>. 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 <a href="F%C3%B6rster_resonance_energy_transfer" title="Förster resonance energy transfer">Förster resonance energy transfer</a> (FRET) efficiency in conjunction with spectrally resolved <a href="Two-photon_microscope" class="mw-redirect" title="Two-photon microscope">two-photon microscope</a>. The distribution of FRET efficiencies are simulated against different models to get the geometry and stoichiometry of the complexes.<a href="#cite_note-26">[26]</a>

<div class="mw-heading mw-heading2"><h2 id="Assembly">Assembly</h2></div>

Proper assembly of multiprotein complexes is important, since misassembly can lead to disastrous consequences.<a href="#cite_note-27">[27]</a> In order to study pathway assembly, researchers look at intermediate steps in the pathway. One such technique that allows one to do that is <a href="Electrospray_mass_spectrometry" class="mw-redirect" title="Electrospray mass spectrometry">electrospray mass spectrometry</a>, which can identify different intermediate states simultaneously. This has led to the discovery that most complexes follow an ordered assembly pathway.<a href="#cite_note-pmid23582331-28">[28]</a> 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.<a href="#cite_note-29">[29]</a>

The structure of proteins play a role in how the multiprotein complex assembles. The interfaces between proteins can be used to predict assembly pathways.<a href="#cite_note-pmid23582331-28">[28]</a> The intrinsic flexibility of proteins also plays a role: more flexible proteins allow for a greater surface area available for interaction.<a href="#cite_note-30">[30]</a>

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.

<div class="mw-heading mw-heading3"><h3 id="Evolutionary_significance_of_multiprotein_complex_assembly">Evolutionary significance of multiprotein complex assembly</h3></div>

In homomultimeric complexes, the <a href="Homomeric" title="Homomeric">homomeric</a> proteins assemble in a way that mimics evolution. That is, an intermediate in the assembly process is present in the complex's evolutionary history.<a href="#cite_note-31">[31]</a>

The opposite phenomenon is observed in heteromultimeric complexes, where gene fusion occurs in a manner that preserves the original assembly pathway.<a href="#cite_note-pmid23582331-28">[28]</a>

<ul><li><a href="Heterotetramer" class="mw-redirect" title="Heterotetramer">Heterotetramer</a></li>

<li><a href="Biomolecular_complex" class="mw-redirect" title="Biomolecular complex">Biomolecular complex</a></li>

<li><a href="Protein_subunit" title="Protein subunit">Protein subunit</a></li></ul>

<div class="mw-heading mw-heading2"><h2 id="References">References</h2></div>

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<li id="cite_note-31"><a href="#cite_ref-31">^</a> <cite id="CITEREFLevyBoeri_ErbaRobinsonTeichmann2008" class="citation journal cs1">Levy, Emmanuel D; Boeri Erba, Elisabetta; Robinson, Carol V; Teichmann, Sarah A (July 2008). <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658002">"Assembly reflects evolution of protein complexes"</a>. Nature. 453 (7199): 1262–5. <a href="Bibcode_(identifier)" class="mw-redirect" title="Bibcode (identifier)">Bibcode</a>:<a rel="nofollow" class="external text" href="https://ui.adsabs.harvard.edu/abs/2008Natur.453.1262L">2008Natur.453.1262L</a>. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1038%2Fnature06942">10.1038/nature06942</a>. <a href="PMC_(identifier)" class="mw-redirect" title="PMC (identifier)">PMC</a> <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658002">2658002</a>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/18563089">18563089</a>.</cite>

</li>

</ol></div>

<div class="mw-heading mw-heading2"><h2 id="External_links">External links</h2></div>

<ul><li><a rel="nofollow" class="external text" href="https://meshb.nlm.nih.gov/record/ui?name=Multiprotein+Complexes">Multiprotein+Complexes</a> at the U.S. National Library of Medicine <a href="Medical_Subject_Headings" title="Medical Subject Headings">Medical Subject Headings</a> (MeSH)</li></ul>

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</style><div id="Proteins36" style="font-size:114%;margin:0 4em"><a href="Protein" title="Protein">Proteins</a></div></th></tr><tr><th scope="row" class="navbox-group" style="width:1%">Processes</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Protein_biosynthesis" title="Protein biosynthesis">Protein biosynthesis</a></li>

<li><a href="Post-translational_modification" title="Post-translational modification">Post-translational modification</a></li>

<li><a href="Protein_folding" title="Protein folding">Protein folding</a></li>

<li><a href="Protein_targeting" title="Protein targeting">Protein targeting</a></li>

<li><a href="Proteome" title="Proteome">Proteome</a></li>

<li><a href="Protein_methods" title="Protein methods">Protein methods</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Structures</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Protein_structure" title="Protein structure">Protein structure</a></li>

<li><a href="Protein_domain" title="Protein domain">Protein structural domains</a></li>

<li><a href="Proteasome" title="Proteasome">Proteasome</a></li></ul>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Types</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="List_of_proteins" title="List of proteins">List of proteins</a></li>

<li><a href="Membrane_protein" title="Membrane protein">Membrane protein</a></li>

<li><a href="Globular_protein" title="Globular protein">Globular protein</a>

<ul><li><a href="Globulin" title="Globulin">Globulin</a></li>

<li><a href="Edestin" title="Edestin">Edestin</a></li>

<li><a href="Albumin" title="Albumin">Albumin</a></li></ul></li>

<li><a href="Scleroprotein" class="mw-redirect" title="Scleroprotein">Fibrous protein</a></li>

<li><a href="Chromoprotein" title="Chromoprotein">Chromoprotein</a></li>

<li><a href="Photoreceptor_protein" title="Photoreceptor protein">Photoreceptor protein</a></li>

<li><a href="Biliprotein" title="Biliprotein">Biliprotein</a>

<ul><li><a href="Phycobiliprotein" title="Phycobiliprotein">Phycobiliprotein</a></li>

<li><a href="Phytochrome" title="Phytochrome">Phytochrome</a></li>

<li><a href="Lipocalin" title="Lipocalin">Lipocalin</a></li></ul></li></ul>

</div></td></tr></tbody></table></div>

<div class="navbox-styles"></div><div role="navigation" class="navbox" aria-labelledby="Enzymes:_multienzyme_complexes94" style="padding:3px"><table class="nowraplinks mw-collapsible autocollapse navbox-inner" style="border-spacing:0;background:transparent;color:inherit"><tbody><tr><th scope="col" class="navbox-title" colspan="2"><div id="Enzymes:_multienzyme_complexes94" style="font-size:114%;margin:0 4em"><a href="Enzyme" title="Enzyme">Enzymes</a>: </div></th></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Photosynthesis" title="Photosynthesis">Photosynthesis</a></th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Photosynthetic_reaction_centre" title="Photosynthetic reaction centre">Photosynthetic reaction center complex proteins</a></li>

<li><a href="Photosystem" title="Photosystem">Photosystem</a>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%"><a href="Dehydrogenase" title="Dehydrogenase">Dehydrogenase</a></th><td class="navbox-list-with-group navbox-list navbox-even hlist" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="2-oxoadipate_dehydrogenase_complex" title="2-oxoadipate dehydrogenase complex">2-oxoadipate dehydrogenase complex</a>

<ul><li><a href="DHTKD1" title="DHTKD1">DHTKD1</a></li>

<li><a href="Branched-chain_alpha-keto_acid_dehydrogenase_complex" title="Branched-chain alpha-keto acid dehydrogenase complex">Branched-chain alpha-keto acid dehydrogenase complex</a>

<ul><li><a href="BCKDHA" title="BCKDHA">BCKDHA</a></li>

<li><a href="BCKDHB" title="BCKDHB">BCKDHB</a></li>

<li><a href="Pyruvate_dehydrogenase_complex" title="Pyruvate dehydrogenase complex">Pyruvate dehydrogenase complex</a>

<li><a href="Oxoglutarate_dehydrogenase_complex" title="Oxoglutarate dehydrogenase complex">Oxoglutarate dehydrogenase</a>

</div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%">Other</th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em">

<ul><li><a href="Carbamoyl_phosphate_synthase_II" title="Carbamoyl phosphate synthase II">Carbamoyl phosphate synthase II</a></li>

<li><a href="Aspartate_carbamoyltransferase" title="Aspartate carbamoyltransferase">Aspartate carbamoyltransferase</a></li>

<li><a href="Dihydroorotase" title="Dihydroorotase">Dihydroorotase</a></li></ul></li>

<li><a href="P450-containing_systems" title="P450-containing systems">P450-containing systems</a></li>

<li><a href="Cytochrome_b6f_complex" title="Cytochrome b6f complex">Cytochrome b6f complex</a></li>

<li><a href="Electron_transport_chain" title="Electron transport chain">Electron transport chain</a></li>

<li><a href="Fatty_acid_synthase" title="Fatty acid synthase">Fatty acid synthetase complex</a></li>

<li><a href="Glycine_cleavage_system" title="Glycine cleavage system">Glycine decarboxylase complex</a></li>

<li><a href="Mitochondrial_trifunctional_protein" title="Mitochondrial trifunctional protein">Mitochondrial trifunctional protein</a>

<ul><li><a href="HADHA" title="HADHA">HADHA</a></li>

<li><a href="HADHB" title="HADHB">HADHB</a></li></ul></li>

<li><a href="PEP_group_translocation" title="PEP group translocation">Phosphoenolpyruvate sugar phosphotransferase system</a></li>

<li><a href="Polyketide_synthase" title="Polyketide synthase">Polyketide synthase</a></li>

<li><a href="Sucrase-isomaltase" title="Sucrase-isomaltase">Sucrase-isomaltase complex</a></li>

<li><a href="Tryptophan_synthase" title="Tryptophan synthase">Tryptophan synthase</a></li></ul>

</div></td></tr></tbody></table></div></div><div><div class="zim-footer">

This article is issued from <a class="external text" title="Last edited on 2025-06-02" href="https://en.wikipedia.org/wiki/?title=Protein_complex&oldid=1293524181">Wikipedia</a>. The text is available under <a class="external text" href="https://creativecommons.org/licenses/by-sa/4.0/deed.en">Creative Commons Attribution-Share Alike 4.0</a> unless otherwise noted. Additional terms may apply for the media files.

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