Fuzziness enables context dependence of protein interactions

Proteins may undergo adaptive structural transitions to accommodate to their cellular milieu and respond to external signals. Modulation of conformational ensembles can rewire the intra‐ or intermolecular interaction networks and shift between different functional states. Adaptive conformational transitions are associated with protein fuzziness, which enables (a) rewiring interaction networks via alternative motifs, (b) new functional features via allosteric motifs, (c) functional switches upon post‐translational modifications, or (d) regulation of higher‐order organizations. We propose that all these context‐dependent functional changes are intertwined with structural multiplicity or dynamic disorder in protein assemblies and can only be described by stochastic structure–function relationships.

[1]  A. Bowie,et al.  Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. , 2012, Immunity.

[2]  Xinqi Gong,et al.  Structural insights into RIP3-mediated necroptotic signaling. , 2013, Cell reports.

[3]  Norman E. Davey,et al.  Linear motifs confer functional diversity onto splice variants , 2012, Nucleic acids research.

[4]  Márton Miskei,et al.  FuzDB: database of fuzzy complexes, a tool to develop stochastic structure-function relationships for protein complexes and higher-order assemblies , 2016, Nucleic Acids Res..

[5]  B. Sankaran,et al.  Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins , 2016, Proceedings of the National Academy of Sciences.

[6]  Peter Tompa,et al.  Polymer physics of intracellular phase transitions , 2015, Nature Physics.

[7]  C. Brangwynne,et al.  Nuclear bodies: the emerging biophysics of nucleoplasmic phases. , 2015, Current opinion in cell biology.

[8]  Xinchen Wang,et al.  Tissue-specific alternative splicing remodels protein-protein interaction networks. , 2012, Molecular cell.

[9]  A. Dunker,et al.  Disorder and sequence repeats in hub proteins and their implications for network evolution. , 2006, Journal of proteome research.

[10]  J. Qin,et al.  Structural basis for the phosphorylation-regulated focal adhesion targeting of type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma) by talin. , 2006, Journal of Molecular Biology.

[11]  Eric T. Wang,et al.  Alternative Isoform Regulation in Human Tissue Transcriptomes , 2008, Nature.

[12]  Katherine A. Fitzgerald,et al.  Unified Polymerization Mechanism for the Assembly of ASC-Dependent Inflammasomes , 2014, Cell.

[13]  István Simon,et al.  Preformed structural elements feature in partner recognition by intrinsically unstructured proteins. , 2004, Journal of molecular biology.

[14]  Steven Hahn,et al.  A sequence-specific transcription activator motif and powerful synthetic variants that bind Mediator using a fuzzy protein interface , 2014, Proceedings of the National Academy of Sciences.

[15]  N. Sonenberg,et al.  Interaction of the eukaryotic initiation factor 4E with 4E-BP2 at a dynamic bipartite interface. , 2013, Structure.

[16]  Roy Parker,et al.  Formation and Maturation of Phase-Separated Liquid Droplets by RNA-Binding Proteins. , 2015, Molecular cell.

[17]  A Keith Dunker,et al.  Alternative splicing of intrinsically disordered regions and rewiring of protein interactions. , 2013, Current opinion in structural biology.

[18]  Steven Hahn,et al.  The Acidic Transcription Activator Gcn4 Binds the Mediator Subunit Gal11/med15 Using a Simple Protein Interface Forming a Fuzzy Complex , 2022 .

[19]  Christopher J. Oldfield,et al.  Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners , 2008, BMC Genomics.

[20]  Pietro De Camilli,et al.  Recruitment and regulation of phosphatidylinositol phosphate kinase type 1γ by the FERM domain of talin , 2002, Nature.

[21]  Nam-Chul Ha,et al.  Mechanism of Phosphorylation-Dependent Binding of APC to β-Catenin and Its Role in β-Catenin Degradation , 2004 .

[22]  P. Tompa,et al.  Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. , 2008, Trends in biochemical sciences.

[23]  Monika Fuxreiter,et al.  Fuzzy complexes: a more stochastic view of protein function. , 2012, Advances in experimental medicine and biology.

[24]  Leander M. Sinanan,et al.  An intrinsically disordered region of methyl-CpG binding domain protein 2 (MBD2) recruits the histone deacetylase core of the NuRD complex , 2015, Nucleic acids research.

[25]  Chao Zhang,et al.  The unfolded protein response signals through high-order assembly of Ire1 , 2009, Nature.

[26]  P. Tompa,et al.  Malleable machines take shape in eukaryotic transcriptional regulation. , 2008, Nature chemical biology.

[27]  Monika Fuxreiter,et al.  Fuzzy complexes: Specific binding without complete folding , 2015, FEBS letters.

[28]  R. Nussinov,et al.  The origin of allosteric functional modulation: multiple pre-existing pathways. , 2009, Structure.

[29]  M. Ota,et al.  Two Distinct Mechanisms for Actin Capping Protein Regulation—Steric and Allosteric Inhibition , 2010, PLoS biology.

[30]  H. Dyson,et al.  Intrinsically disordered proteins in cellular signalling and regulation , 2014, Nature Reviews Molecular Cell Biology.

[31]  C. Brangwynne,et al.  The disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics , 2015, Proceedings of the National Academy of Sciences.

[32]  A. Arnold,et al.  Differential distribution of the MeCP2 splice variants in the postnatal mouse brain , 2007, The Journal of comparative neurology.

[33]  J. Qin,et al.  Structural basis for the phosphorylation-regulated focal adhesion targeting of type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma) by talin. , 2006, Journal of molecular biology.

[34]  Stuart A. Wilson,et al.  Competitive and Cooperative Interactions Mediate RNA Transfer from Herpesvirus Saimiri ORF57 to the Mammalian Export Adaptor ALYREF , 2014, PLoS pathogens.

[35]  M. Madan Babu,et al.  A million peptide motifs for the molecular biologist. , 2014, Molecular cell.

[36]  V. Hilser,et al.  The ensemble nature of allostery , 2014, Nature.

[37]  Hao Wu,et al.  Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2 , 2015, Cell Discovery.

[38]  Zhijian J. Chen,et al.  Prion-like Polymerization Underlies Signal Transduction in Antiviral Immune Defense and Inflammasome Activation , 2014, Cell.

[39]  L. Kay,et al.  Variable Control of Ets-1 DNA Binding by Multiple Phosphates in an Unstructured Region , 2005, Science.

[40]  Nicolas L. Fawzi,et al.  Residue-by-Residue View of In Vitro FUS Granules that Bind the C-Terminal Domain of RNA Polymerase II. , 2015, Molecular cell.

[41]  M. Blackledge,et al.  Plasticity of an Ultrafast Interaction between Nucleoporins and Nuclear Transport Receptors , 2015, Cell.

[42]  Alan M. Moses,et al.  Short linear motifs – ex nihilo evolution of protein regulation , 2015, Cell Communication and Signaling.

[43]  M. Bienz.  Signalosome assembly by domains undergoing dynamic head-to-tail polymerization. , 2014, Trends in biochemical sciences.

[44]  Peter E. Wright,et al.  Modulation of allostery by protein intrinsic disorder , 2013, Nature.

[45]  Y. Liu,et al.  Internal regulatory interactions determine DNA binding specificity by a Hox transcription factor. , 2009, Journal of molecular biology.

[46]  Hongtao Yu,et al.  Structural basis for the binding of proline-rich peptides to SH3 domains , 1994, Cell.

[47]  Andrew L. Lee,et al.  Supertertiary structure of the MAGUK core from PSD-95. , 2013, Structure.

[48]  Monika Fuxreiter,et al.  The Structure and Dynamics of Higher-Order Assemblies: Amyloids, Signalosomes, and Granules , 2016, Cell.

[49]  Joseph R. Nevins,et al.  A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells , 2004, Nature Cell Biology.

[50]  Michael Krauss,et al.  Molecular Basis for Association of PIPKIγ-p90 with Clathrin Adaptor AP-2* , 2009, The Journal of Biological Chemistry.

[51]  Mike Tyers,et al.  Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor , 2008, Proceedings of the National Academy of Sciences.

[52]  S. Richard,et al.  Arginine methylation by PRMT1 regulates nuclear-cytoplasmic localization and toxicity of FUS/TLS harbouring ALS-linked mutations. , 2012, Human molecular genetics.

[53]  Monika Fuxreiter,et al.  Fuzziness: linking regulation to protein dynamics. , 2012, Molecular bioSystems.

[54]  Nam-Chul Ha,et al.  Mechanism of phosphorylation-dependent binding of APC to beta-catenin and its role in beta-catenin degradation. , 2004, Molecular cell.

[55]  L. Kay,et al.  Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch , 2014, Nature.

[56]  A Keith Dunker,et al.  Intrinsically disordered proteins and intrinsically disordered protein regions. , 2014, Annual review of biochemistry.

[57]  Maria Sunnerhagen,et al.  Biophysical properties of regions flanking the bHLH-Zip motif in the p22 Max protein. , 2004, Biochemical and biophysical research communications.

[58]  V. Hilser,et al.  Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins , 2007, Proceedings of the National Academy of Sciences.

[59]  F. Sicheri,et al.  Structure of the Dual Enzyme Ire1 Reveals the Basis for Catalysis and Regulation in Nonconventional RNA Splicing , 2008, Cell.

[60]  T. Nilsen,et al.  Expansion of the eukaryotic proteome by alternative splicing , 2010, Nature.

[61]  Jens Meiler,et al.  A Derived Allosteric Switch Underlies the Evolution of Conditional Cooperativity between HOXA11 and FOXO1. , 2016, Cell reports.

[62]  Alex Bateman,et al.  Tissue-Specific Splicing of Disordered Segments that Embed Binding Motifs Rewires Protein Interaction Networks , 2012, Molecular cell.

[63]  G. Harauz,et al.  The proline-rich region of 18.5 kDa myelin basic protein binds to the SH3-domain of Fyn tyrosine kinase with the aid of an upstream segment to form a dynamic complex in vitro , 2014, Bioscience reports.

[64]  Gergely Katona,et al.  Structural Basis of Ribosomal S6 Kinase 1 (RSK1) Inhibition by S100B Protein , 2015, The Journal of Biological Chemistry.

[65]  S. Lindquist,et al.  Structural insights into a yeast prion illuminate nucleation and strain diversity , 2005, Nature.

[66]  Ying Liu,et al.  Multiple Intrinsically Disordered Sequences Alter DNA Binding by the Homeodomain of the Drosophila Hox Protein Ultrabithorax* , 2008, Journal of Biological Chemistry.

[67]  D. Barford,et al.  Conformational diversity in the TPR domain-mediated interaction of protein phosphatase 5 with Hsp90. , 2006, Structure.

[68]  Monika Fuxreiter,et al.  Dynamic Protein–dna Recognition: beyond What Can Be Seen , 2022 .

[69]  Ruedi Aebersold,et al.  Dual Specificity Kinase DYRK3 Couples Stress Granule Condensation/Dissolution to mTORC1 Signaling , 2013, Cell.

[70]  Vincent J. Lynch,et al.  Evolution of a derived protein–protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation , 2011, Proceedings of the National Academy of Sciences.

[71]  Terje Johansen,et al.  The selective autophagy receptor p62 forms a flexible filamentous helical scaffold. , 2015, Cell reports.

[72]  Timothy D. Craggs,et al.  Phase Transition of a Disordered Nuage Protein Generates Environmentally Responsive Membraneless Organelles , 2015, Molecular cell.

[73]  Julie D. Forman-Kay,et al.  Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding , 2012, Nucleic acids research.

[74]  Hao Wu,et al.  Higher-Order Assemblies in a New Paradigm of Signal Transduction , 2013, Cell.

[75]  George Harauz,et al.  Binding of the proline-rich segment of myelin basic protein to SH3 domains: spectroscopic, microarray, and modeling studies of ligand conformation and effects of posttranslational modifications. , 2008, Biochemistry.

[76]  H. Dyson,et al.  Linking folding and binding. , 2009, Current opinion in structural biology.

[77]  Monika Fuxreiter,et al.  Interactions via intrinsically disordered regions: What kind of motifs? , 2012, IUBMB life.

[78]  Christopher J. Oldfield,et al.  Classification of Intrinsically Disordered Regions and Proteins , 2014, Chemical reviews.

[79]  Norman E. Davey,et al.  Attributes of short linear motifs. , 2012, Molecular bioSystems.

[80]  D. Kern,et al.  Dynamic personalities of proteins , 2007, Nature.

[81]  Paul S. Russo,et al.  Phase Transitions in the Assembly of MultiValent Signaling Proteins , 2016 .

[82]  William T Heller,et al.  Role of intrinsic flexibility in signal transduction mediated by the cell cycle regulator, p27 Kip1. , 2008, Journal of molecular biology.

[83]  Kenta Moriwaki,et al.  The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex Required for Programmed Necrosis , 2012, Cell.