title: A conserved N-terminal motif is required for complex formation between FUS, EWSR1, TAF15 and their oncogenic fusion proteins.
abstract: The three FET (FUS, EWSR1, and TAF15) family RNA binding proteins are expressed in all tissues and almost all cell types. The disordered N-terminal parts are always present in FET fusion oncoproteins of sarcomas and leukemia. Mutations in FUS and TAF15 cause aggregation of FET proteins in neurological disorders. Here we used recombinant proteins in pulldown experiments and mass spectrometry to identify major interaction partners of the FET N-terminal parts. We report that FUS, EWSR1, and TAF15 form homo- and heterocomplexes as major binding partners and identify an evolutionarily conserved N-terminal motif (FETBM1) that is required for this interaction. The binding is RNA and DNA independent and robust up to 1 M of NaCl. The localization of FETBM1 and its target sequences supports a simple model for FET protein aggregation as reported in neurological disorders such as amyotrophic lateral sclerosis, frontotemporal dementia, and essential tremor. The FETBM1 localization also explains the binding of normal full-length FET proteins to their oncogenic fusion proteins.
authors: 1Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Box 425, 40530, Gothenburg, Sweden. pierre.aman@llcr.med.gu.se.
authors: Christer
authors: C
authors: Thomsen
authors: Pernilla
authors: P
authors: Grundevik
authors: Per
authors: P
authors: Elias
authors: Anders
authors: A
authors: Ståhlberg
authors: Pierre
authors: P
authors: Aman
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D002148:Calmodulin-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS / Q000737:chemistry* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D035381:TATA-Binding Protein Associated Factors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002148:Calmodulin-Binding Proteins; C500986:EWSR1 protein, human; D015514:Oncogene Proteins, Fusion; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins; C102041:TAF15 protein, human; D035381:TATA-Binding Protein Associated Factors
keywords: neurodegenerative diseases; neuropathology; tumor biology