Protein intrinsic disorder and network connectivity. The case of 14-3-3 proteins

The understanding of networks is a common goal of an unprecedented array of traditional disciplines. One of the protein network properties most influenced by the structural contents of its nodes is the inter-connectivity. Recent studies in which structural information was included into the topological analysis of protein networks revealed that the content of intrinsic disorder in the nodes could modulate the network topology, rewire networks, and change their inter-connectivity, which is defined by its clustering coefficient. Here, we review the role of intrinsic disorder present in the partners of the highly conserved 14-3-3 protein family on its interaction networks. The 14-3-3s are phospho-serine/threonine binding proteins that have strong influence in the regulation of metabolism and signal transduction networks. Intrinsic disorder increases the clustering coefficients, namely the inter-connectivity of the nodes within each 14-3-3 paralog networks. We also review two new ideas to measure intrinsic disorder independently of the primary sequence of proteins, a thermodynamic model and a method that uses protein structures and their solvent environment. This new methods could be useful to explain unsolved questions about versatility and fixation of intrinsic disorder through evolution. The relation between the intrinsic disorder and network topologies could be an interesting model to investigate new implicitness of the graph theory into biology.

[1]  James R Faeder,et al.  Toward a quantitative theory of intrinsically disordered proteins and their function , 2009, Proceedings of the National Academy of Sciences.

[2]  L. Bi,et al.  Identification of novel 14-3-3ζ interacting proteins by quantitative immunoprecipitation combined with knockdown (QUICK). , 2010, Journal of proteome research.

[3]  P. Allen,et al.  Interaction of 14-3-3 with Signaling Proteins Is Mediated by the Recognition of Phosphoserine , 1996, Cell.

[4]  M. Uhart,et al.  Human 14-3-3 Paralogs Differences Uncovered by Cross-Talk of Phosphorylation and Lysine Acetylation , 2013, PloS one.

[5]  D. Morrison,et al.  The 14-3-3 proteins: integrators of diverse signaling cues that impact cell fate and cancer development. , 2009, Trends in cell biology.

[6]  Javier De Las Rivas,et al.  Protein–Protein Interactions Essentials: Key Concepts to Building and Analyzing Interactome Networks , 2010, PLoS Comput. Biol..

[7]  J. S. Sodhi,et al.  Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. , 2004, Journal of molecular biology.

[8]  M. Yaffe,et al.  Structural determinants of 14-3-3 binding specificities and regulation of subcellular localization of 14-3-3-ligand complexes: a comparison of the X-ray crystal structures of all human 14-3-3 isoforms. , 2006, Seminars in cancer biology.

[9]  Jianmin Wu,et al.  Integrated network analysis platform for protein-protein interactions , 2009, Nature Methods.

[10]  Michael B Yaffe,et al.  14-3-3 Proteins--a focus on cancer and human disease. , 2004, Journal of molecular and cellular cardiology.

[11]  J Günter Grossmann,et al.  Structural basis for protein–protein interactions in the 14-3-3 protein family , 2006, Proceedings of the National Academy of Sciences.

[12]  Niall J. Haslam,et al.  Understanding eukaryotic linear motifs and their role in cell signaling and regulation. , 2008, Frontiers in bioscience : a journal and virtual library.

[13]  Patrick Aloy,et al.  The Role of Structural Disorder in the Rewiring of Protein Interactions through Evolution* , 2012, Molecular & Cellular Proteomics.

[14]  E. P. Kennedy,et al.  The enzymatic phosphorylation of proteins. , 1954, The Journal of biological chemistry.

[15]  A. Dunker,et al.  Understanding protein non-folding. , 2010, Biochimica et biophysica acta.

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

[17]  Marc S. Cortese,et al.  Flexible nets , 2005, The FEBS journal.

[18]  D. M. Bustos,et al.  The role of protein disorder in the 14-3-3 interaction network. , 2012, Molecular bioSystems.

[19]  A. Aitken.  14-3-3 proteins: a historic overview. , 2006, Seminars in cancer biology.

[20]  Jianzhi Zhang,et al.  Rapid Subfunctionalization Accompanied by Prolonged and Substantial Neofunctionalization in Duplicate Gene Evolution , 2005, Genetics.

[21]  N. Gusev,et al.  Oligomeric structure of 14‐3‐3 protein: What do we know about monomers? , 2012, FEBS letters.

[22]  R. Liddington.  Structural basis of protein-protein interactions. , 2015, Methods in molecular biology.

[23]  Zhaolei Zhang,et al.  An atlas of chaperone–protein interactions in Saccharomyces cerevisiae: implications to protein folding pathways in the cell , 2009, Molecular systems biology.

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

[25]  Alan M. Moses,et al.  Proteome-Wide Discovery of Evolutionary Conserved Sequences in Disordered Regions , 2012, Science Signaling.

[26]  C. Ottmann,et al.  Molecular tweezers modulate 14-3-3 protein-protein interactions. , 2013, Nature chemistry.

[27]  Peter Tompa,et al.  Unstructural biology coming of age. , 2011, Current opinion in structural biology.

[28]  D. Shakes,et al.  Molecular evolution of the 14-3-3 protein family , 1996, Journal of Molecular Evolution.

[29]  S. Vajda,et al.  Anchor residues in protein-protein interactions. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

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

[31]  D. Campbell,et al.  14-3-3-affinity purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation and trafficking. , 2004, The Biochemical journal.

[32]  A. Antson,et al.  Monomeric 14-3-3ζ Has a Chaperone-Like Activity and Is Stabilized by Phosphorylated HspB6 , 2012, Biochemistry.

[33]  C. Cheng,et al.  14-3-3 and its binding partners are regulators of protein-protein interactions during spermatogenesis. , 2009, The Journal of endocrinology.

[34]  Philip M. Kim,et al.  The role of disorder in interaction networks: a structural analysis , 2008, Molecular systems biology.

[35]  Pedro Beltrão,et al.  Comparative Genomics and Disorder Prediction Identify Biologically Relevant SH3 Protein Interactions , 2005, PLoS Comput. Biol..

[36]  N. Gough,et al.  Focus Issue: Systems Analysis of Protein Phosphorylation , 2010, Science Signaling.

[37]  S. Teichmann,et al.  Tight Regulation of Unstructured Proteins: From Transcript Synthesis to Protein Degradation , 2008, Science.

[38]  A. Iglesias,et al.  Structurally constrained residues outside the binding motif are essential in the interaction of 14-3-3 and phosphorylated partner. , 2011, Journal of molecular biology.

[39]  Michael B Yaffe,et al.  How do 14‐3‐3 proteins work? – Gatekeeper phosphorylation and the molecular anvil hypothesis , 2002, FEBS letters.

[40]  M. Tinti,et al.  Evolution of signal multiplexing by 14-3-3-binding 2R-ohnologue protein families in the vertebrates , 2012, Open Biology.

[41]  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.

[42]  Ariel Fernández,et al.  Nonadaptive origins of interactome complexity , 2011, Nature.

[43]  E. Skoulakis,et al.  Dimerization Is Essential for 14-3-3ζ Stability and Function in Vivo* , 2009, The Journal of Biological Chemistry.

[44]  R. Kleppe,et al.  Does isoform diversity explain functional differences in the 14-3-3 protein family? , 2006, Current pharmaceutical biotechnology.

[45]  A K Dunker,et al.  Protein disorder and the evolution of molecular recognition: theory, predictions and observations. , 1998, Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing.

[46]  Tao Shen,et al.  A Combined Proteome and Ultrastructural Localization Analysis of 14-3-3 Proteins in Transformed Human Amnion (AMA) Cells , 2008, Molecular & Cellular Proteomics.

[47]  Duncan J. Watts,et al.  Collective dynamics of ‘small-world’ networks , 1998, Nature.

[48]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[49]  Alastair Aitken,et al.  Functional specificity in 14-3-3 isoform interactions through dimer formation and phosphorylation. Chromosome location of mammalian isoforms and variants. , 2002, Plant Molecular Biology.

[50]  Christopher J. Oldfield,et al.  The unfoldomics decade: an update on intrinsically disordered proteins , 2008, BMC Genomics.

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

[52]  S. Hsu,et al.  Subfunctionalization reduces the fitness cost of gene duplication in humans by buffering dosage imbalances , 2011, BMC Genomics.

[53]  Fiona C. Denison,et al.  14-3-3 phosphoprotein interaction networks – does isoform diversity present functional interaction specification? , 2012, Front. Plant Sci..

[54]  A. Iglesias,et al.  Intrinsic disorder is a key characteristic in partners that bind 14‐3‐3 proteins , 2006, Proteins.

[55]  Luisa Montecchi-Palazzi,et al.  Combining peptide recognition specificity and context information for the prediction of the 14‐3‐3‐mediated interactome in S. cerevisiae and H. sapiens , 2011, Proteomics.

[56]  L. Iakoucheva,et al.  The importance of intrinsic disorder for protein phosphorylation. , 2004, Nucleic acids research.

[57]  D. Campbell,et al.  Bioinformatic and experimental survey of 14-3-3-binding sites , 2010, The Biochemical journal.

[58]  István Simon,et al.  BIOINFORMATICS ORIGINAL PAPER doi:10.1093/bioinformatics/btm035 Structural bioinformatics Local structural disorder imparts plasticity on linear motifs , 2022 .

[59]  Vladimir N. Uversky,et al.  The roles of intrinsic disorder in protein interaction networks , 2013 .

[60]  F. D. Carlson.  Physiological and Biochemical Aspects of Nervous Integration , 1968 .

[61]  Angel F. Lopez,et al.  Sphingosine and FTY720 directly bind pro-survival 14-3-3 proteins to regulate their function. , 2010, Cellular signalling.