fuzzy complex
File:Sic1.png structure of the cyclin-dependent kinase inhibitor Sic1 with the ubiquitin ligase Cdc4 (grey). Out of the nine phosphorylation sites of Sic 1 (spheres) the contacts with T45 and S76 are shown (orange and blue).]]
File:Ubx.png transcription factor (orange) connects the homeodomain with the Extradenticle homeodomain (blue) (PDB code 1bi). Alternative splicing modulates the length of the fuzzy region and thus its DNA (grey) binding affinity. Other regulatory fuzzy regions of Ultrabithorax are also shown by dotted lines.]]
Fuzzy complexes are protein complexes, where structural ambiguity or multiplicity exists and is required for biological function.{{cite journal |doi=10.1016/j.tibs.2007.10.003 |pmid=18054235 |title=Fuzzy complexes: Polymorphism and structural disorder in protein–protein interactions |journal=Trends in Biochemical Sciences |volume=33 |issue=1 |pages=2–8 |year=2008 |last1=Tompa |first1=Peter |last2=Fuxreiter |first2=Monika }}Fuxreiter, M. & Tompa, P. (2011) Fuzziness: Structural Disorder in Protein Complexes Austin, New York.{{pn|date=February 2018}} Alteration, truncation or removal of conformationally ambiguous regions impacts the activity of the corresponding complex.{{cite journal |doi=10.1126/science.1111915 |pmid=15994560 |title=Variable Control of Ets-1 DNA Binding by Multiple Phosphates in an Unstructured Region |journal=Science |volume=309 |issue=5731 |pages=142–5 |year=2005 |last1=Pufall |first1=M. A |last2=Lee |first2=Gregory M |last3=Nelson |first3=Mary L |last4=Kang |first4=Hyun-Seo |last5=Velyvis |first5=Algirdas |last6=Kay |first6=Lewis E |last7=McIntosh |first7=Lawrence P |last8=Graves |first8=Barbara J |bibcode=2005Sci...309..142P |doi-access=free }}{{cite journal |doi=10.1126/science.1120941 |pmid=16424299 |title=The Ste5 Scaffold Allosterically Modulates Signaling Output of the Yeast Mating Pathway |journal=Science |volume=311 |issue=5762 |pages=822–6 |year=2006 |last1=Bhattacharyya |first1=R. P |last2=Reményi |first2=Attila |last3=Good |first3=Matthew C |last4=Bashor |first4=Caleb J |last5=Falick |first5=Arnold M |last6=Lim |first6=Wendell A |bibcode=2006Sci...311..822B |s2cid=13882487 |doi-access=free }}{{cite journal |doi=10.1016/j.jmb.2009.05.059 |pmid=19481089 |pmc=2739810 |title=Internal Regulatory Interactions Determine DNA Binding Specificity by a Hox Transcription Factor |journal=Journal of Molecular Biology |volume=390 |issue=4 |pages=760–74 |year=2009 |last1=Liu |first1=Ying |last2=Matthews |first2=Kathleen S |last3=Bondos |first3=Sarah E }} Fuzzy complexes are generally formed by intrinsically disordered proteins.{{cite journal |pmid=9697202 |url=http://psb.stanford.edu/psb-online/proceedings/psb98/abstracts/p437.html |year=1998 |last1=Romero |first1=P |title=Thousands of proteins likely to have long disordered regions |journal=Pacific Symposium on Biocomputing |pages=437–48 |last2=Obradovic |first2=Z |last3=Kissinger |first3=C. R |last4=Villafranca |first4=J. E |last5=Garner |first5=E |last6=Guilliot |first6=S |last7=Dunker |first7=A. K }}{{cite journal |doi=10.1006/jmbi.1999.3110 |pmid=10550212 |title=Intrinsically unstructured proteins: Re-assessing the protein structure-function paradigm |journal=Journal of Molecular Biology |volume=293 |issue=2 |pages=321–31 |year=1999 |last1=Wright |first1=Peter E |authorlink2=Jane Dyson|last2=Dyson |first2=H. Jane }} Structural multiplicity usually underlies functional multiplicity of protein complexes {{cite journal |doi=10.1016/j.jmb.2007.12.016 |pmid=18177895 |pmc=2350195 |title=Role of Intrinsic Flexibility in Signal Transduction Mediated by the Cell Cycle Regulator, p27Kip1 |journal=Journal of Molecular Biology |volume=376 |issue=3 |pages=827–38 |year=2008 |last1=Galea |first1=Charles A |last2=Nourse |first2=Amanda |last3=Wang |first3=Yuefeng |last4=Sivakolundu |first4=Sivashankar G |last5=Heller |first5=William T |last6=Kriwacki |first6=Richard W }}{{cite journal |doi=10.1038/nchembio.127 |pmid=19008886 |pmc=2921704 |title=Malleable machines take shape in eukaryotic transcriptional regulation |journal=Nature Chemical Biology |volume=4 |issue=12 |pages=728–37 |year=2008 |last1=Fuxreiter |first1=Monika |last2=Tompa |first2=Peter |last3=Simon |first3=István |last4=Uversky |first4=Vladimir N |last5=Hansen |first5=Jeffrey C |last6=Asturias |first6=Francisco J }}{{cite journal |doi=10.1038/nchembio.536 |pmid=21358637 |pmc=3124363 |title=Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21 |journal=Nature Chemical Biology |volume=7 |issue=4 |pages=214–21 |year=2011 |last1=Wang |first1=Yuefeng |last2=Fisher |first2=John C |last3=Mathew |first3=Rose |last4=Ou |first4=Li |last5=Otieno |first5=Steve |last6=Sublet |first6=Jack |last7=Xiao |first7=Limin |last8=Chen |first8=Jianhan |last9=Roussel |first9=Martine F |last10=Kriwacki |first10=Richard W }} following a fuzzy logic. Distinct binding modes of the nucleosome are also regarded as a special case of fuzziness.{{cite journal |doi=10.1371/journal.pone.0012984 |pmid=20886052 |pmc=2945322 |title=Weakly Positioned Nucleosomes Enhance the Transcriptional Competency of Chromatin |journal=PLOS ONE |volume=5 |issue=9 |pages=e12984 |year=2010 |last1=Belch |first1=Yaakov |last2=Yang |first2=Jingyi |last3=Liu |first3=Yang |last4=Malkaram |first4=Sridhar A |last5=Liu |first5=Rong |last6=Riethoven |first6=Jean-Jack M |last7=Ladunga |first7=Istvan |bibcode=2010PLoSO...512984B |doi-access=free }}{{cite journal |doi=10.1128/MCB.05276-11 |pmid=21896781 |pmc=3209338 |title=Evolution of Nucleosome Occupancy: Conservation of Global Properties and Divergence of Gene-Specific Patterns |journal=Molecular and Cellular Biology |volume=31 |issue=21 |pages=4348–55 |year=2011 |last1=Tsui |first1=K |last2=Dubuis |first2=S |last3=Gebbia |first3=M |last4=Morse |first4=R. H |last5=Barkai |first5=N |last6=Tirosh |first6=I |last7=Nislow |first7=C }}
Historical background
For almost 50 years molecular biology was based on two dogmas: (i) equating biological function of the protein with a unique three-dimensional structure and (ii) assuming exquisite specificity in protein complexes. Specificity/selectivity is ensured by unambiguous set of interactions formed between the protein and its ligand (another protein, DNA, RNA or small molecule). Many protein complexes however, contain functionally important/critical regions, which remain highly dynamic in the complex or adopt different conformations.{{cite journal |doi=10.1039/c1mb05234a |pmid=21927770 |title=Fuzziness: Linking regulation to protein dynamics |journal=Molecular BioSystems |volume=8 |issue=1 |pages=168–77 |year=2012 |last1=Fuxreiter |first1=Monika }} This phenomenon is defined fuzziness. The most pertinent example is the cyclin-dependent kinase inhibitor Sic1, which binds to the SCF subunit of Cdc4 in a phosphorylation dependent manner.{{cite journal |doi=10.1038/35107009 |pmid=11734846 |title=Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication |journal=Nature |volume=414 |issue=6863 |pages=514–21 |year=2001 |last1=Nash |first1=Piers |last2=Tang |first2=Xiaojing |last3=Orlicky |first3=Stephen |last4=Chen |first4=Qinghua |last5=Gertler |first5=Frank B |last6=Mendenhall |first6=Michael D |last7=Sicheri |first7=Frank |last8=Pawson |first8=Tony |last9=Tyers |first9=Mike |bibcode=2001Natur.414..514N |s2cid=16924667 }} No regular secondary structures are gained upon phosphorylation and the different phosphorylation sites interchange in the complex.{{cite journal |doi=10.1073/pnas.0809222105 |jstor=25465359 |pmid=19008353 |pmc=2582940 |title=Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor |journal=Proceedings of the National Academy of Sciences |volume=105 |issue=46 |pages=17772–7 |year=2008 |last1=Mittag |first1=T |last2=Orlicky |first2=S |last3=Choy |first3=W.-Y |last4=Tang |first4=X |last5=Lin |first5=H |last6=Sicheri |first6=F |last7=Kay |first7=L. E |last8=Tyers |first8=M |last9=Forman-Kay |first9=J. D |bibcode=2008PNAS..10517772M |doi-access=free }}
Classification of fuzzy complexes
Structural ambiguity in protein complexes covers a wide spectrum. In a polymorphic complex, the protein adopts two or more different conformations upon binding to the same partner, and these conformations can be resolved.{{cite journal |doi=10.1038/emboj.2011.461 |pmid=22193718 |pmc=3280557 |title=How a single residue in individual β-thymosin/WH2 domains controls their functions in actin assembly |journal=The EMBO Journal |volume=31 |issue=4 |pages=1000–13 |year=2012 |last1=Didry |first1=Dominique |last2=Cantrelle |first2=Francois-Xavier |last3=Husson |first3=Clotilde |last4=Roblin |first4=Pierre |last5=Moorthy |first5=Anna M Eswara |last6=Perez |first6=Javier |last7=Le Clainche |first7=Christophe |last8=Hertzog |first8=Maud |last9=Guittet |first9=Eric |last10=Carlier |first10=Marie-France |last11=Van Heijenoort |first11=Carine |last12=Renault |first12=Louis }} Clamp,{{cite journal |doi=10.1006/jmbi.2000.3642 |pmid=10764582 |title=Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-α |journal=Journal of Molecular Biology |volume=297 |issue=5 |pages=1183–94 |year=2000 |last1=Fontes |first1=Marcos R.M |last2=Teh |first2=Trazel |last3=Kobe |first3=Bostjan }} flanking {{cite journal |doi=10.1074/jbc.M207361200 |pmid=12196545 |title=Roles of Phosphorylation and Helix Propensity in the Binding of the KIX Domain of CREB-binding Protein by Constitutive (c-Myb) and Inducible (CREB) Activators |journal=Journal of Biological Chemistry |volume=277 |issue=44 |pages=42241–8 |year=2002 |last1=Zor |first1=Tsaffrir |last2=Mayr |first2=Bernhard M |last3=Dyson |first3=H. Jane |last4=Montminy |first4=Marc R |last5=Wright |first5=Peter E |doi-access=free }}{{cite journal |doi=10.1016/S1097-2765(03)00115-1 |pmid=12718882 |title=Structural Basis for the Molecular Recognition between Human Splicing Factors U2AF65 and SF1/mBBP |journal=Molecular Cell |volume=11 |issue=4 |pages=965–76 |year=2003 |last1=Selenko |first1=Philipp |last2=Gregorovic |first2=Goran |last3=Sprangers |first3=Remco |last4=Stier |first4=Gunter |last5=Rhani |first5=Zakaria |last6=Krämer |first6=Angela |last7=Sattler |first7=Michael |doi-access=free }} and random complexes{{cite journal |doi=10.1074/jbc.M310948200 |pmid=14625282 |title=Quantitative Observation of Backbone Disorder in Native Elastin |journal=Journal of Biological Chemistry |volume=279 |issue=9 |pages=7982–7 |year=2004 |last1=Pometun |first1=Maxim S |last2=Chekmenev |first2=Eduard Y |last3=Wittebort |first3=Richard J |doi-access=free }}{{cite journal |doi=10.1021/bi035900h |pmid=14967045 |title=Homooligomerization of the Cytoplasmic Domain of the T Cell Receptor ζ Chain and of Other Proteins Containing the Immunoreceptor Tyrosine-Based Activation Motif |journal=Biochemistry |volume=43 |issue=7 |pages=2049–61 |year=2004 |last1=Sigalov |first1=Alexander |last2=Aivazian |first2=Dikran |last3=Stern |first3=Lawrence }} are dynamic, where ambiguous conformations interchange with each other and cannot be resolved. Interactions in fuzzy complexes are usually mediated by short motifs.{{cite journal |doi=10.1016/j.tibs.2010.10.002 |pmid=21146412 |title=How viruses hijack cell regulation |journal=Trends in Biochemical Sciences |volume=36 |issue=3 |pages=159–69 |year=2011 |last1=Davey |first1=Norman E |last2=Travé |first2=Gilles |last3=Gibson |first3=Toby J }} Flanking regions are tolerant to sequence changes as long as the amino acid composition is maintained, for example in case of linker histone C-terminal domains {{cite journal |doi=10.1021/bi801636y |pmid=19072710 |pmc=2644900 |title=Chromatin Condensing Functions of the Linker Histone C-Terminal Domain Are Mediated by Specific Amino Acid Composition and Intrinsic Protein Disorder |journal=Biochemistry |volume=48 |issue=1 |pages=164–72 |year=2009 |last1=Lu |first1=Xu |last2=Hamkalo |first2=Barbara |last3=Parseghian |first3=Missag H |last4=Hansen |first4=Jeffrey C }} and H4 histone N-terminal domains.{{cite journal |doi=10.1074/jbc.M109.011288 |pmid=19395382 |pmc=2719306 |title=Determinants of Histone H4 N-terminal Domain Function during Nucleosomal Array Oligomerization |journal=Journal of Biological Chemistry |volume=284 |issue=25 |pages=16716–22 |year=2009 |last1=McBryant |first1=Steven J |last2=Klonoski |first2=Joshua |last3=Sorensen |first3=Troy C |last4=Norskog |first4=Sarah S |last5=Williams |first5=Sere |last6=Resch |first6=Michael G |last7=Toombs |first7=James A |last8=Hobdey |first8=Sarah E |last9=Hansen |first9=Jeffrey C |doi-access=free }}
Regulatory pathways via fuzzy regions
Fuzzy regions modulate the conformational equilibrium {{cite journal |doi=10.1021/bi0500729 |pmid=16171389 |title=Structural and Thermodynamical Characterization of the Complete p21 Gene Product of Max |journal=Biochemistry |volume=44 |issue=38 |pages=12746–58 |year=2005 |last1=Naud |first1=Jean-François |last2=McDuff |first2=François-Olivier |last3=Sauvé |first3=Simon |last4=Montagne |first4=Martin |last5=Webb |first5=Bradley A |last6=Smith |first6=Steven P |last7=Chabot |first7=Benoit |last8=Lavigne |first8=Pierre }} or flexibility {{cite journal |doi=10.1016/j.jmb.2008.07.064 |pmid=18692067 |pmc=4808631 |title=The Affinity of Ets-1 for DNA is Modulated by Phosphorylation Through Transient Interactions of an Unstructured Region |journal=Journal of Molecular Biology |volume=382 |issue=4 |pages=1014–30 |year=2008 |last1=Lee |first1=Gregory M |last2=Pufall |first2=Miles A |last3=Meeker |first3=Charles A |last4=Kang |first4=Hyun-Seo |last5=Graves |first5=Barbara J |last6=McIntosh |first6=Lawrence P }} of the binding interface via transient interactions.{{cite journal |doi=10.1016/j.tibs.2011.04.006 |pmid=21620710 |title=Dynamic protein–DNA recognition: Beyond what can be seen |journal=Trends in Biochemical Sciences |volume=36 |issue=8 |pages=415–23 |year=2011 |last1=Fuxreiter |first1=Monika |last2=Simon |first2=Istvan |last3=Bondos |first3=Sarah }} Dynamic regions can also compete with binding sites{{cite journal |doi=10.1016/j.jmb.2007.09.075 |pmid=17988686 |title=Mapping Intramolecular Interactions between Domains in HMGB1 using a Tail-truncation Approach |journal=Journal of Molecular Biology |volume=374 |issue=5 |pages=1286–97 |year=2007 |last1=Watson |first1=Matthew |last2=Stott |first2=Katherine |last3=Thomas |first3=Jean O }} or tether them to the target.{{cite journal |doi=10.1080/07391102.2005.10507052 |pmid=16060685 |title=Secondary Structure and Dynamics of an Intrinsically Unstructured Linker Domain |journal=Journal of Biomolecular Structure and Dynamics |volume=23 |issue=2 |pages=113–24 |year=2005 |last1=Olson |first1=Katie E |last2=Narayanaswami |first2=Pranesh |last3=Vise |first3=Pamela D |last4=Lowry |first4=David F |last5=Wold |first5=Marc S |last6=Daughdrill |first6=Gary W |s2cid=37429006 }} Modifications of fuzzy regions by further interactions,{{cite journal |doi=10.1016/j.bpj.2008.10.003 |pmid=19134474 |pmc=2710047 |title=Induced Secondary Structure and Polymorphism in an Intrinsically Disordered Structural Linker of the CNS: Solid-State NMR and FTIR Spectroscopy of Myelin Basic Protein Bound to Actin |journal=Biophysical Journal |volume=96 |issue=1 |pages=180–91 |year=2009 |last1=Ahmed |first1=Mumdooh A.M |last2=Bamm |first2=Vladimir V |last3=Shi |first3=Lichi |last4=Steiner-Mosonyi |first4=Marta |last5=Dawson |first5=John F |last6=Brown |first6=Leonid |last7=Harauz |first7=George |last8=Ladizhansky |first8=Vladimir |bibcode=2009BpJ....96..180A }} or posttranslational modifications{{cite journal |doi=10.1111/j.1742-4658.2006.05165.x |pmid=16689930 |title=Gradual phosphorylation regulates PC4 coactivator function |journal=FEBS Journal |volume=273 |issue=7 |pages=1430–44 |year=2006 |last1=Jonker |first1=Hendrik R. A |last2=Wechselberger |first2=Rainer W |last3=Pinkse |first3=Martijn |last4=Kaptein |first4=Robert |last5=Folkers |first5=Gert E |hdl=1874/19762 |s2cid=38856641 |hdl-access=free }}{{cite journal |doi=10.1074/jbc.M109.001958 |pmid=19605348 |pmc=2782050 |title=Phosphorylated Intrinsically Disordered Region of FACT Masks Its Nucleosomal DNA Binding Elements |journal=Journal of Biological Chemistry |volume=284 |issue=36 |pages=24610–21 |year=2009 |last1=Tsunaka |first1=Yasuo |last2=Toga |first2=Junko |last3=Yamaguchi |first3=Hiroto |last4=Tate |first4=Shin-Ichi |last5=Hirose |first5=Susumu |last6=Morikawa |first6=Kosuke |doi-access=free }} impact binding affinity or specificity. Alternative splicing can modulate the length of fuzzy regions resulting in context-dependent binding (e.g. tissue-specificity) on the complex.{{cite journal |doi=10.1074/jbc.M212057200 |pmid=12816948 |title=Regulation of the NEDD8 Conjugation System by a Splicing Variant, NUB1L |journal=Journal of Biological Chemistry |volume=278 |issue=35 |pages=32905–13 |year=2003 |last1=Tanaka |first1=Tomoaki |last2=Kawashima |first2=Hidenori |last3=Yeh |first3=Edward T. H |last4=Kamitani |first4=Tetsu |doi-access=free }}{{cite journal |doi=10.1074/jbc.M800375200 |pmid=18508761 |pmc=2475714 |title=Multiple Intrinsically Disordered Sequences Alter DNA Binding by the Homeodomain of the Drosophila Hox Protein Ultrabithorax |journal=Journal of Biological Chemistry |volume=283 |issue=30 |pages=20874–87 |year=2008 |last1=Liu |first1=Ying |last2=Matthews |first2=Kathleen S |last3=Bondos |first3=Sarah E |doi-access=free }}{{cite journal |doi=10.1073/pnas.1100990108 |pmid=21788518 |pmc=3156161 |title=Evolution of a derived protein-protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation |journal=Proceedings of the National Academy of Sciences |volume=108 |issue=32 |pages=E414–20 |year=2011 |last1=Brayer |first1=K. J |last2=Lynch |first2=V. J |last3=Wagner |first3=G. P |bibcode=2011PNAS..108E.414B |doi-access=free }} EGF/MAPK, TGF-β and WNT/Wingless signaling pathways employ tissue-specific fuzzy regions.
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