title: Principles of self-organization in biological pathways: a hypothesis on the autogenous association of alpha-synuclein.
abstract: 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.
authors.affiliation: Gene Function and Evolution, Bioinformatics and Genomics, Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain and Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zanzoni
authors.forename: Domenica
authors.initials: D
authors.lastname: Marchese
authors.forename: Federico
authors.initials: F
authors.lastname: Agostini
authors.forename: Benedetta
authors.initials: B
authors.lastname: Bolognesi
authors.forename: Davide
authors.initials: D
authors.lastname: Cirillo
authors.forename: Maria
authors.initials: M
authors.lastname: Botta-Orfila
authors.forename: Carmen Maria
authors.initials: CM
authors.lastname: Livi
authors.forename: Silvia
authors.initials: S
authors.lastname: Rodriguez-Mulero
authors.forename: Gian Gaetano
authors.initials: GG
authors.lastname: Tartaglia
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D005786:Gene Expression Regulation; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D012313:RNA / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D064267:Intrinsically Disordered Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D016159:Tumor Suppressor Protein p53; D051844:alpha-Synuclein; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D012313:RNA