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      Molecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1

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          Abstract

          Human hnRNP A2/B1 is an RNA-binding protein that plays important roles in many biological processes, including maturation, transport, and metabolism of mRNA, and gene regulation of long noncoding RNAs. hnRNP A2/B1 was reported to control the microRNAs sorting to exosomes and promote primary microRNA processing as a potential m 6A “reader.” hnRNP A2/B1 contains two RNA recognition motifs that provide sequence-specific recognition of RNA substrates. Here, we determine crystal structures of tandem RRM domains of hnRNP A2/B1 in complex with various RNA substrates, elucidating specific recognitions of AGG and UAG motifs by RRM1 and RRM2 domains, respectively. Further structural and biochemical results demonstrate multivariant binding modes for sequence-diversified RNA substrates, supporting a RNA matchmaker mechanism in hnRNP A2/B1 function. Moreover, our studies in combination with bioinformatic analysis suggest that hnRNP A2/B1 may mediate effects of m 6A through a “m 6A switch” mechanism, instead of acting as a direct “reader” of m 6A modification.

          Abstract

          RNA-binding protein hnRNP A2/B1 is suggested to promote miRNA processing as a m 6A 'reader'. Here, the authors determine crystal structures of RRM domains of hnRNP A2/B1 in complex with various RNA substrates and determine that hnRNP A2/B1 may function as an auxiliary factor in 'm 6A switch' instead.

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          Most cited references23

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          RNA regulons: coordination of post-transcriptional events.

          Jack Keene (2007)
          Recent findings demonstrate that multiple mRNAs are co-regulated by one or more sequence-specific RNA-binding proteins that orchestrate their splicing, export, stability, localization and translation. These and other observations have given rise to a model in which mRNAs that encode functionally related proteins are coordinately regulated during cell growth and differentiation as post-transcriptional RNA operons or regulons, through a ribonucleoprotein-driven mechanism. Here I describe several recently discovered examples of RNA operons in budding yeast, fruitfly and mammalian cells, and their potential importance in processes such as immune response, oxidative metabolism, stress response, circadian rhythms and disease. I close by considering the evolutionary wiring and rewiring of these combinatorial post-transcriptional gene-expression networks.
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            RBPDB: a database of RNA-binding specificities

            The RNA-Binding Protein DataBase (RBPDB) is a collection of experimental observations of RNA-binding sites, both in vitro and in vivo, manually curated from primary literature. To build RBPDB, we performed a literature search for experimental binding data for all RNA-binding proteins (RBPs) with known RNA-binding domains in four metazoan species (human, mouse, fly and worm). In total, RPBDB contains binding data on 272 RBPs, including 71 that have motifs in position weight matrix format, and 36 sets of sequences of in vivo-bound transcripts from immunoprecipitation experiments. The database is accessible by a web interface which allows browsing by domain or by organism, searching and export of records, and bulk data downloads. Users can also use RBPDB to scan sequences for RBP-binding sites. RBPDB is freely available, without registration at http://rbpdb.ccbr.utoronto.ca/.
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              RNA-binding proteins with prion-like domains in health and disease.

              Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid-liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, including TDP-43 (transactivation response element DNA-binding protein 43), FUS (fused in sarcoma), TAF15 (TATA-binding protein-associated factor 15), EWSR1 (Ewing sarcoma breakpoint region 1), and heterogeneous nuclear ribonucleoproteins A1 and A2 (hnRNPA1 and hnRNPA2), have now been connected via pathology and genetics to the etiology of several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Here, we review the physiological and pathological roles of the most prominent RBPs with PrLDs. We also highlight the potential of protein disaggregases, including Hsp104, as a therapeutic strategy to combat the aberrant phase transitions of RBPs with PrLDs that likely underpin neurodegeneration.
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                Author and article information

                Contributors
                majb@fudan.edu.cn
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                29 January 2018
                29 January 2018
                2018
                : 9
                : 420
                Affiliations
                [1 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, State Key Laboratory of Genetic Engineering, Collaborative Innovation Centre of Genetics and Development, Department of Biochemistry, Institute of Plant Biology, School of Life Sciences, , Fudan University, ; Shanghai, 200438 China
                [2 ]ISNI 000000041936877X, GRID grid.5386.8, Department of Pharmacology, Weill Cornell Medicine, , Cornell University, ; New York, NY 10065 USA
                [3 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Biophysics, School of Life Sciences, , Fudan University, ; Shanghai, 200438 China
                Author information
                http://orcid.org/0000-0003-3615-6958
                http://orcid.org/0000-0002-0232-1786
                Article
                2770
                10.1038/s41467-017-02770-z
                5789076
                29379020
                3494807a-b411-4105-82ab-8c1f17d711a8
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 June 2017
                : 22 December 2017
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