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Fuzzy complex
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<h2 id="historical-background">Historical background</h2> <p>For almost 50 years <a href="/facts/Molecular_biology/YgqU35ub">molecular biology</a> was based on two dogmas: (i) equating biological function of the protein with a unique three-dimensional <a href="/facts/Protein_structure/BptnTs9X">structure</a> and (ii) assuming exquisite specificity in protein <a href="/facts/Multiprotein_complexes/ukuyKJfj">complexes</a>. Specificity/selectivity is ensured by unambiguous set of <a href="/facts/Protein-protein_interaction/etvm9Wmg">interactions</a> formed between the protein and its ligand (another <a href="/facts/Protein/Jxmagu3E">protein</a>, <a href="/facts/DNA/nB89Iauz">DNA</a>, <a href="/facts/RNA/HxPeNfNj">RNA</a> or <a href="/facts/Small_molecule/kbwq3VBn">small molecule</a>). Many <a href="/facts/Multiprotein_complexes/ukuyKJfj">protein complexes</a> however, contain functionally important/critical regions, which remain highly dynamic in the complex or adopt different <a href="/facts/Protein_structure/BptnTs9X">conformations</a>.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> This phenomenon is defined fuzziness. The most pertinent example is the <a href="/facts/Cyclin-dependent_kinase_inhibitor_protein/uK79DGS2">cyclin-dependent kinase inhibitor</a> <a href="/facts/Sic1/glmmlgdN">Sic1</a>, which binds to the SCF subunit of <a href="/facts/Cell_division_control_protein_4/FId9moBI">Cdc4</a> in a <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a> dependent manner.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> No regular secondary structures are gained upon <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a> and the different phosphorylation sites interchange in the complex.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p> <h2 id="classification-of-fuzzy-complexes">Classification of fuzzy complexes</h2> <p>Structural ambiguity in protein complexes covers a wide spectrum.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> In a polymorphic complex, the protein adopts two or more different conformations upon binding to the same partner, and these conformations can be resolved.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Clamp,<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> flanking <a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> and random complexes<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> are dynamic, where ambiguous conformations interchange with each other and cannot be resolved. <a href="/facts/Protein-protein_interactions/etvm9Wmg">Interactions</a> in fuzzy complexes are usually mediated by <a href="/facts/Short_linear_motif/EqU80U6g">short motifs</a>.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> Flanking regions are tolerant to sequence changes as long as the <a href="/facts/Amino_acid/WDxYwBny">amino acid</a> composition is maintained, for example in case of linker <a href="/facts/Histone/krb5VJfp">histone</a> C-terminal domains <a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> and H4 <a href="/facts/Histone/krb5VJfp">histone</a> N-terminal domains.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p> <h2 id="regulatory-pathways-via-fuzzy-regions">Regulatory pathways via fuzzy regions</h2> <p>Fuzzy regions modulate the conformational equilibrium <a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> or flexibility <a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> of the binding interface via <a href="/facts/Multiprotein_complex/GW11Ee34">transient interactions</a>.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> Dynamic regions can also compete with binding sites<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> or tether them to the target.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> Modifications of fuzzy regions by further interactions,<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a><a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> or <a href="/facts/Posttranslational_modifications/KMUayTIc">posttranslational modifications</a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a><a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> impact <a href="/facts/Binding_affinity/44QLL4eU">binding affinity</a> or specificity. <a href="/facts/Alternative_splicing/nNRwPVNK">Alternative splicing</a> can modulate the length of fuzzy regions resulting in context-dependent binding (e.g. <a href="/facts/Tissue_(biology)/H7CpML7A">tissue</a>-specificity) on the complex.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a><a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a><a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> <a href="/facts/Epidermal_growth_factor/CpyH5tYs">EGF</a>/<a href="/facts/Mitogen-activated_protein_kinase/YdDS5KkU">MAPK</a>, <a href="/facts/Transforming_growth_factor_beta/6bD65SWQ">TGF-β</a> and <a href="/facts/Wnt_signaling_pathway/7wxpKrjy">WNT/Wingless</a> <a href="/facts/Signal_transduction/1bs0Me6w">signaling pathways</a> employ tissue-specific fuzzy regions. </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Tompa, Peter; Fuxreiter, Monika (2008). 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