Principles of self-organization in biological pathways: a hypothesis on the autogenous association of alpha-synuclein

Previous evidence indicates that a number of proteins are able to interact with cognate mRNAs. These autogenous associations represent important regulatory mechanisms that control gene expression at the translational level. Using the catRAPID approach to predict the propensity of proteins to bind to RNA, we investigated the occurrence of autogenous associations in the human proteome. Our algorithm correctly identified binding sites in well-known cases such as thymidylate synthase, tumor suppressor P53, synaptotagmin-1, serine/ariginine-rich splicing factor 2, heat shock 70 kDa, ribonucleic particle-specific U1A and ribosomal protein S13. In addition, we found that several other proteins are able to bind to their own mRNAs. A large-scale analysis of biological pathways revealed that aggregation-prone and structurally disordered proteins have the highest propensity to interact with cognate RNAs. These findings are substantiated by experimental evidence on amyloidogenic proteins such as TAR DNA-binding protein 43 and fragile X mental retardation protein. Among the amyloidogenic proteins, we predicted that Parkinson’s disease-related α-synuclein is highly prone to interact with cognate transcripts, which suggests the existence of RNA-dependent factors in its function and dysfunction. Indeed, as aggregation is intrinsically concentration dependent, it is possible that autogenous interactions play a crucial role in controlling protein homeostasis.

[1]  A. Ivanov,et al.  Human ribosomal protein S13 inhibits splicing of its own pre-mRNA , 2007, Molecular Biology.

[2]  Frederick W. Alt,et al.  DNA Repair, Genome Stability, and Aging , 2005, Cell.

[3]  M. Hegde,et al.  DNA induces folding in alpha-synuclein: understanding the mechanism using chaperone property of osmolytes. , 2007, Archives of biochemistry and biophysics.

[4]  S. Warren,et al.  Local RNA Translation at the Synapse and in Disease , 2011, The Journal of Neuroscience.

[5]  M. Hlevnjak,et al.  Sequence signatures of direct complementarity between mRNAs and cognate proteins on multiple levels , 2012, Nucleic acids research.

[6]  J. Rinn,et al.  Modular regulatory principles of large non-coding RNAs , 2012, Nature.

[7]  P. Tompa,et al.  Janus chaperones: Assistance of both RNA‐ and protein‐folding by ribosomal proteins , 2009, FEBS letters.

[8]  Lincoln Stein,et al.  Reactome: a database of reactions, pathways and biological processes , 2010, Nucleic Acids Res..

[9]  J. Steitz,et al.  The "Observer Effect" in genome-wide surveys of protein-RNA interactions. , 2013, Molecular cell.

[10]  J. Alwine,et al.  Direct interaction of the U1 snRNP-A protein with the upstream efficiency element of the SV40 late polyadenylation signal. , 1994, Genes & development.

[11]  A. Gargouri,et al.  Translational control of human p53 expression in yeast mediated by 5'-UTR-ORF structural interaction. , 2001, Nucleic acids research.

[12]  Michele Vendruscolo,et al.  Life on the edge: a link between gene expression levels and aggregation rates of human proteins. , 2007, Trends in biochemical sciences.

[13]  C. von Mering,et al.  PaxDb, a Database of Protein Abundance Averages Across All Three Domains of Life , 2012, Molecular & Cellular Proteomics.

[14]  F. Hartl,et al.  DnaK functions as a central hub in the E. coli chaperone network. , 2012, Cell reports.

[15]  T. Henics,et al.  Analysis of sequence-specific binding of RNA to Hsp70 and its various homologs indicates the involvement of N- and C-terminal interactions. , 2001, RNA.

[16]  Wendy Noble,et al.  Neurodegeneration as an RNA disorder , 2012, Progress in Neurobiology.

[17]  Federico Agostini,et al.  Predicting protein associations with long noncoding RNAs , 2011, Nature Methods.

[18]  V. Uversky,et al.  Role of Protein−Water Interactions and Electrostatics in α-Synuclein Fibril Formation† , 2004 .

[19]  Jiajie Diao,et al.  Properties of native brain α-synuclein , 2013, Nature.

[20]  D. Herschlag.  RNA Chaperones and the RNA Folding Problem (*) , 1995, The Journal of Biological Chemistry.

[21]  Bronwen L. Aken,et al.  GENCODE: The reference human genome annotation for The ENCODE Project , 2012, Genome research.

[22]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Ben Lehner,et al.  Intrinsic Protein Disorder and Interaction Promiscuity Are Widely Associated with Dosage Sensitivity , 2009, Cell.

[24]  R. Shiekhattar,et al.  Activating RNAs associate with Mediator to enhance chromatin architecture and transcription , 2013, Nature.

[25]  C. Creutz,et al.  Calcium‐Dependent Self‐Association of Synaptotagmin I , 1996, Journal of neurochemistry.

[26]  Nobutoshi Ito,et al.  Crystal structure at 1.92 Å resolution of the RNA-binding domain of the U1A spliceosomal protein complexed with an RNA hairpin , 1994, Nature.

[27]  Zsuzsanna Dosztányi,et al.  IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content , 2005, Bioinform..

[28]  R. Aebersold,et al.  A High-Confidence Human Plasma Proteome Reference Set with Estimated Concentrations in PeptideAtlas* , 2011, Molecular & Cellular Proteomics.

[29]  A. Pastore,et al.  On the aggregation properties of FMRP – a link with the FXTAS syndrome? , 2011, The FEBS journal.

[30]  V. Uversky,et al.  Nuclear Localization of α-Synuclein and Its Interaction with Histones† , 2003 .

[31]  James Stévenin,et al.  Antagonistic factors control the unproductive splicing of SC35 terminal intron , 2009, Nucleic acids research.

[32]  Jernej Ule,et al.  TDP‐43 regulates its mRNA levels through a negative feedback loop , 2011, The EMBO journal.

[33]  Xin Lu.  Tied up in loops: positive and negative autoregulation of p53. , 2010, Cold Spring Harbor perspectives in biology.

[34]  S. Mannava,et al.  Ribonucleotide reductase and thymidylate synthase or exogenous deoxyribonucleosides reduce DNA damage and senescence caused by C-MYC depletion , 2012, Aging.

[35]  Keith W. Caldecott,et al.  Single-strand break repair and genetic disease , 2008, Nature Reviews Genetics.

[36]  R. Edwards,et al.  Lipid rafts mediate the synaptic localization of alpha-synuclein. , 2004, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[37]  Michael J. Devine,et al.  Parkinson's disease and α‐synuclein expression , 2011, Movement disorders : official journal of the Movement Disorder Society.

[38]  T. Südhof,et al.  α-Synuclein Promotes SNARE-Complex Assembly in Vivo and in Vitro , 2010, Science.

[39]  E. Buratti,et al.  TDP-43 Autoregulation: Implications for Disease , 2011, Journal of Molecular Neuroscience.

[40]  N. Lin,et al.  Hsp90 Interacts Specifically with Viral RNA and Differentially Regulates Replication Initiation of Bamboo mosaic virus and Associated Satellite RNA , 2012, PLoS pathogens.

[41]  T. Henics.  Extending the ‘stressy’ edge: molecular chaperones flirting with RNA , 2003, Cell biology international.

[42]  A Sureau,et al.  SC35 autoregulates its expression by promoting splicing events that destabilize its mRNAs , 2001, The EMBO journal.

[43]  V. Uversky,et al.  Nuclear localization of alpha-synuclein and its interaction with histones. , 2003, Biochemistry.

[44]  Federico Agostini,et al.  X-inactivation: quantitative predictions of protein interactions in the Xist network , 2012, Nucleic acids research.

[45]  Robert Edwards,et al.  Lipid Rafts Mediate the Synaptic Localization of α-Synuclein , 2004, The Journal of Neuroscience.

[46]  W. Webb,et al.  Quantification of alpha-synuclein binding to lipid vesicles using fluorescence correlation spectroscopy. , 2006, Biophysical journal.

[47]  Petr Klus,et al.  Neurodegenerative diseases: quantitative predictions of protein-RNA interactions. , 2013, RNA.

[48]  H. Moriya,et al.  Robustness analysis of cellular systems using the genetic tug-of-war method. , 2012, Molecular bioSystems.

[49]  B. Seong,et al.  RNA-mediated chaperone type for de novo protein folding , 2009, RNA biology.

[50]  I. Martin,et al.  Recent advances in the genetics of Parkinson's disease. , 2011, Annual review of genomics and human genetics.

[51]  M. Babu,et al.  Cellular Strategies for Regulating Functional and Nonfunctional Protein Aggregation , 2012, Cell reports.

[52]  J. Harrow,et al.  GENCODE: producing a reference annotation for ENCODE , 2006, Genome Biology.

[53]  Nichole L. King,et al.  Human Plasma PeptideAtlas , 2005, Proteomics.

[54]  P. Csermely,et al.  Mammalian Hsp70 and Hsp110 Proteins Bind to RNA Motifs Involved in mRNA Stability* , 1999, The Journal of Biological Chemistry.

[55]  W. Deppert,et al.  Negative feedback regulation of wild-type p53 biosynthesis , 2007, Journal of Cancer Research and Clinical Oncology.

[56]  V. Rotter,et al.  The role of p53 in base excision repair following genotoxic stress. , 2003, Carcinogenesis.

[57]  G. M. Wilson,et al.  Hsp70 Is a Novel Posttranscriptional Regulator of Gene Expression That Binds and Stabilizes Selected mRNAs Containing AU-Rich Elements , 2012, Molecular and Cellular Biology.

[58]  The UniProt Consortium,et al.  Reorganizing the protein space at the Universal Protein Resource (UniProt) , 2011, Nucleic Acids Res..

[59]  Federico Agostini,et al.  Predictions of protein–RNA interactions , 2013 .

[60]  Xudong Huang,et al.  Selective Translational Control of the Alzheimer Amyloid Precursor Protein Transcript by Iron Regulatory Protein-1*♦ , 2010, The Journal of Biological Chemistry.

[61]  R. Scheller,et al.  Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[62]  M. Hentze,et al.  Enzymes as RNA-binding proteins: a role for (di)nucleotide-binding domains? , 1994, Trends in biochemical sciences.

[63]  Bernard Schneider,et al.  α-Synuclein in Central Nervous System and from Erythrocytes, Mammalian Cells, and Escherichia coli Exists Predominantly as Disordered Monomer* , 2012, The Journal of Biological Chemistry.

[64]  G. Hong,et al.  Nucleic Acids Research , 2015, Nucleic Acids Research.

[65]  K. Anthony,et al.  Aberrant RNA processing events in neurological disorders , 2010, Brain Research.

[66]  J. Silberg,et al.  A transposase strategy for creating libraries of circularly permuted proteins , 2012, Nucleic acids research.

[67]  Joost Schymkowitz,et al.  Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. , 2011, Nature chemical biology.

[68]  G. Varani,et al.  Structural basis of the RNA‐binding specificity of human U1A protein , 1997, The EMBO journal.

[69]  K. Lin,et al.  Inhibition of TDP-43 Aggregation by Nucleic Acid Binding , 2013, PloS one.

[70]  S. Sukumaran,et al.  The cytoplasmic C2A domain of synaptotagmin shows sequence specific interaction with its own mRNA. , 2008, Biochemical and biophysical research communications.

[71]  W. Boelens,et al.  The human U1 snRNP-Specific U1A protein inhibits polyadenylation of its own pre-mRNA , 1993, Cell.

[72]  Janusz M. Bujnicki,et al.  Intrinsic Disorder in the Human Spliceosomal Proteome , 2012, PLoS Comput. Biol..

[73]  Cole Trapnell,et al.  Improving RNA-Seq expression estimates by correcting for fragment bias , 2011, Genome Biology.

[74]  L. Twyffels,et al.  Shuttling SR proteins: more than splicing factors , 2011, The FEBS journal.

[75]  V. Uversky,et al.  Role of protein-water interactions and electrostatics in alpha-synuclein fibril formation. , 2004, Biochemistry.

[76]  G. Maley,et al.  Identification of an RNA binding site for human thymidylate synthase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[77]  References , 1971 .

[78]  Kenneth H. Buetow,et al.  PID: the Pathway Interaction Database , 2008, Nucleic Acids Res..

[79]  S. Supattapone,et al.  RNA molecules stimulate prion protein conversion , 2003, Nature.

[80]  Michael Q. Zhang,et al.  Exonic Splicing Enhancer Motif Recognized by Human SC35 under Splicing Conditions , 2000, Molecular and Cellular Biology.

[81]  Samuel H. Wilson,et al.  A role for p53 in base excision repair , 2001, The EMBO journal.

[82]  N. Pace,et al.  The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme , 1983, Cell.

[83]  Lili Wan,et al.  RNA and Disease , 2009, Cell.

[84]  G. Maley,et al.  Characterization of a specific interaction between Escherichia coli thymidylate synthase and Escherichia coli thymidylate synthase mRNA. , 1995, Nucleic acids research.

[85]  G. Maley,et al.  Thymidylate synthase binds to c-myc RNA in human colon cancer cells and in vitro , 1995, Molecular and cellular biology.

[86]  G. Edelman,et al.  The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[87]  Peter Tompa,et al.  The role of structural disorder in the function of RNA and protein chaperones , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[88]  A. Malygin,et al.  Human ribosomal protein S13: cloning, expression, refolding, and structural stability. , 2005, Biochimica et biophysica acta.

[89]  A. De Maio,et al.  Heat shock protein 70 binds its own messenger ribonucleic acid as part of a gene expression self-limiting mechanism , 2006, Cell stress & chaperones.

[90]  Y. Cordeiro,et al.  Cognate DNA stabilizes the tumor suppressor p53 and prevents misfolding and aggregation. , 2009, Biochemistry.

[91]  K. Collins,et al.  Structured non-coding RNAs and the RNP Renaissance. , 2008, Current opinion in chemical biology.

[92]  V. Subramaniam,et al.  Double-stranded DNA stimulates the fibrillation of alpha-synuclein in vitro and is associated with the mature fibrils: an electron microscopy study. , 2004, Journal of molecular biology.

[93]  K. Ikebukuro,et al.  Selection of DNA aptamers that recognize α-synuclein oligomers using a competitive screening method. , 2012, Analytical chemistry.

[94]  Lilia M. Iakoucheva,et al.  Serine/arginine-rich splicing factors belong to a class of intrinsically disordered proteins , 2006, Nucleic acids research.

[95]  Colin A. Smith,et al.  Induced Folding in RNA–Protein Recognition: More than a Simple Molecular Handshake , 1998, Cell.

[96]  M. Kimmel,et al.  Conflict of interest statement. None declared. , 2010 .

[97]  Norman E. Davey,et al.  Insights into RNA Biology from an Atlas of Mammalian mRNA-Binding Proteins , 2012, Cell.

[98]  S. Sprang,et al.  Structure of the first C2 domain of synaptotagmin I: A novel Ca2+/phospholipid-binding fold , 1995, Cell.

[99]  C. Ehresmann,et al.  The fragile X mental retardation protein binds specifically to its mRNA via a purine quartet motif , 2001, The EMBO journal.

[100]  W. Webb,et al.  Quantification of α-Synuclein Binding to Lipid Vesicles Using Fluorescence Correlation Spectroscopy , 2006 .

[101]  Michele Vendruscolo,et al.  Metastability of native proteins and the phenomenon of amyloid formation. , 2011, Journal of the American Chemical Society.

[102]  Lila M Gierasch,et al.  Conserved, Disordered C Terminus of DnaK Enhances Cellular Survival upon Stress and DnaK in Vitro Chaperone Activity* , 2011, The Journal of Biological Chemistry.

[103]  A. Dunker,et al.  Intrinsically disordered regions of p53 family are highly diversified in evolution. , 2013, Biochimica et biophysica acta.

[104]  C. Woese.  The genetic code : the molecular basis for genetic expression , 1967 .

[105]  C R Woese,et al.  The molecular basis for the genetic code. , 1966, Proceedings of the National Academy of Sciences of the United States of America.

[106]  P. Dennis,et al.  Autogenous control: ribosomal protein L10‐L12 complex binds to the leader sequence of its mRNA. , 1982, The EMBO journal.

[107]  P. Chan,et al.  Extensive nuclear localization of α-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody , 2007, Neuroscience.

[108]  Z Benyó,et al.  A common periodic table of codons and amino acids. , 2003, Biochemical and biophysical research communications.

[109]  S. Melov,et al.  Selective binding of nuclear alpha-synuclein to the PGC1alpha promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: implications for Parkinson's disease. , 2012, Free radical biology & medicine.