A low-complexity region in the YTH domain protein Mmi1 enhances RNA binding

Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype–phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid–liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights into the pathogenesis and potential therapeutic targets of FTLD.

Download Full-text

Genome-wide Identification and Expression Analysis of the YTH Domain-containing RNA-binding Protein Family in Citrus Sinensis

Journal of the American Society for Horticultural Science ◽

10.21273/jashs04567-18 ◽

2019 ◽

Vol 144 (2) ◽

pp. 79-91 ◽

Cited By ~ 1

Author(s):

Zhigang Ouyang ◽

Huihui Duan ◽

Lanfang Mi ◽

Wei Hu ◽

Jianmei Chen ◽

...

Keyword(s):

Stress Responses ◽

Messenger Rna ◽

Citrus Sinensis ◽

Rna Binding ◽

Developmental Stages ◽

Rna Binding Proteins ◽

Expression Profiles ◽

Expression Patterns ◽

Genome Wide ◽

Yth Domain

In eukaryotic systems, messenger RNA regulations, including splicing, 3′-end formation, editing, localization, and translation, are achieved by different RNA-binding proteins and noncoding RNAs. The YTH domain is a newly identified RNA-binding domain that was identified by comparing its sequence with that of splicing factor YT521-B. Previous study showed that the YTH gene plays an important role in plant resistance to abiotic and biotic stress. In this study, 211 YTH genes were identified in 26 species that represent four major plant lineages. Phylogenetic analysis revealed that these genes could be divided into eight subgroups. All of the YTH genes contain a YT521 domain and have different structures. Ten YTH genes were identified in navel orange (Citrus sinensis). The expression profiles of these CitYTH genes were analyzed in different tissues and at different fruit developmental stages, and CitYTH genes displayed distinct expression patterns under heat, cold, salt, and drought stress. Furthermore, expression of the CitYTH genes in response to exogenous hormones was measured. Nuclear localization was also confirmed for five of the proteins encoded by these genes after transient expression in Nicotiana benthamiana cells. This study provides valuable information on the role of CitYTHs in the signaling pathways involved in environmental stress responses in Citrus.

Download Full-text

The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation

Cells ◽

10.3390/cells9081791 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1791

Author(s):

Ana Bajc Česnik ◽

Helena Motaln ◽

Boris Rogelj

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Rna Binding ◽

Neurodegenerative Disorder ◽

Low Complexity ◽

Wild Type ◽

Disease Heterogeneity ◽

Cytoplasmic Inclusions ◽

The Impact ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder, characterized by cytoplasmic inclusions of RNA-binding protein TDP-43. Despite decades of research and identification of more than 50 genes associated with amyotrophic lateral sclerosis (ALS), the cause of TDP-43 translocation from the nucleus and its aggregation in the cytoplasm still remains unknown. Our study addressed the impact of selected ALS-associated genes on TDP-43 aggregation behavior in wild-type and aggregation prone TDP-43 in vitro cell models. These were developed by deleting TDP-43 nuclear localization signal and stepwise shortening its low-complexity region. The SH-SY5Y cells were co-transfected with the constructs of aggregation-prone TDP-43 and wild-type or mutant ALS-associated genes hnRNPA1, MATR3, VCP or UBQLN2. The investigated genes displayed a unique impact on TDP-43 aggregation, generating distinct types of cytoplasmic inclusions, similar to those already described as resembling prion strains, which could represent the basis for neurodegenerative disease heterogeneity.

Download Full-text

RNA-binding proteins with prion-like domains in health and disease

Biochemical Journal ◽

10.1042/bcj20160499 ◽

2017 ◽

Vol 474 (8) ◽

pp. 1417-1438 ◽

Cited By ~ 152

Author(s):

Alice Ford Harrison ◽

James Shorter

Keyword(s):

Phase Transitions ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Protein ◽

Low Complexity ◽

Fused In Sarcoma ◽

Heterogeneous Nuclear Ribonucleoproteins ◽

Health And Disease ◽

Lateral Sclerosis

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.

Download Full-text

NMR Structural Study of TcUBP1, a Single RRM Domain Protein fromTrypanosoma cruzi: Contribution of a β Hairpin to RNA Binding†,‡

Biochemistry ◽

10.1021/bi047450e ◽

2005 ◽

Vol 44 (10) ◽

pp. 3708-3717 ◽

Cited By ~ 25

Author(s):

Laurent Volpon ◽

Iván D'Orso ◽

Christopher R. Young ◽

Alberto C. Frasch ◽

Kalle Gehring

Keyword(s):

Structural Study ◽

Rna Binding ◽

Rrm Domain ◽

Domain Protein

Download Full-text

The YTH Domain Protein ECT2 Is an m6A Reader Required for Normal Trichome Branching in Arabidopsis

The Plant Cell ◽

10.1105/tpc.17.00854 ◽

2018 ◽

Vol 30 (5) ◽

pp. 986-1005 ◽

Cited By ~ 42

Author(s):

Jérémy Scutenaire ◽

Jean-Marc Deragon ◽

Viviane Jean ◽

Moussa Benhamed ◽

Cécile Raynaud ◽

...

Keyword(s):

Yth Domain ◽

Domain Protein

Download Full-text

A New Method for Determining Structure Ensemble: Application to a RNA Binding Di-Domain Protein

Biophysical Journal ◽

10.1016/j.bpj.2016.04.009 ◽

2016 ◽

Vol 110 (9) ◽

pp. 1943-1956 ◽

Cited By ~ 7

Author(s):

Wei Liu ◽

Jingfeng Zhang ◽

Jing-Song Fan ◽

Giancarlo Tria ◽

Gerhard Grüber ◽

...

Keyword(s):

Rna Binding ◽

New Method ◽

Domain Protein ◽

Structure Ensemble

Download Full-text

Reconstitution of Targeted Deadenylation by the Ccr4-Not Complex and the YTH Domain Protein Mmi1

Cell Reports ◽

10.1016/j.celrep.2016.10.066 ◽

2016 ◽

Vol 17 (8) ◽

pp. 1978-1989 ◽

Cited By ~ 31

Author(s):

James A.W. Stowell ◽

Michael W. Webster ◽

Alexander Kögel ◽

Jana Wolf ◽

Kathryn L. Shelley ◽

...

Keyword(s):

Yth Domain ◽

Domain Protein

Download Full-text

Redox-mediated regulation of a labile, evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain

10.1101/2019.12.24.885962 ◽

2019 ◽

Author(s):

Yi Lin ◽

Xiaoming Zhou ◽

Masato Kato ◽

Daifei Liu ◽

Sina Ghaemmaghami ◽

...

Keyword(s):

Rna Binding ◽

Thioredoxin Reductase ◽

Methionine Sulfoxide ◽

Low Complexity ◽

Methionine Sulfoxide Reductase ◽

Methionine Residue ◽

Low Concentrations ◽

Evolutionarily Conserved ◽

Methionine Residues ◽

Self Association

SummaryAn evolutionarily conserved low complexity (LC) domain is found within a 152 residue segment localized to the carboxyl-terminal region of the TDP43 RNA-binding protein. This TDP43 LC domain contains ten conserved methionine residues. Self-association of this domain leads to the formation of liquid-like droplets composed of labile, cross-β polymers. Exposure of polymers to low concentrations of H2O2 leads to a phenomenon of droplet melting that can be reversed upon exposure of the oxidized protein to the MsrA and MsrB methionine sulfoxide reductase enzymes, thioredoxin, thioredoxin reductase and NADPH. Morphological features of the cross-β polymers were revealed by a method of H2O2-mediated footprinting. Similar TDP43 LC domain footprints were observed in highly polymerized, hydrogel samples, liquid-like droplet samples, and living cells. The ability of H2O2 to impede cross-β polymerization was abrogated by a prominent ALS-causing mutation that changes methionine residue 337 to valine. These observations offer potentially useful insight into the biological role of TDP43 in facilitating synapse-localized translation, as well as aberrant aggregation of the protein in neurodegenerative disease.

Download Full-text

Proteomic analysis of Dhh1 complexes reveals a role for Hsp40 chaperone Ydj1 in yeast P-body assembly

10.1101/016402 ◽

2015 ◽

Author(s):

Gregory A. Cary ◽

Dani B.N. Vinh ◽

Patrick May ◽

Rolf Kuestner ◽

Aimee M. Dudley

Keyword(s):

Rna Binding ◽

Rna Binding Proteins ◽

Active Role ◽

Low Complexity ◽

Mitochondrial Rna ◽

P Bodies ◽

Glucose Depletion ◽

Catalytic Rnas ◽

Rnp Granules

P-bodies (PB) are ribonucleoprotein (RNP) complexes that aggregate into cytoplasmic foci when cells are exposed to stress. While the conserved mRNA decay and translational repression machineries are known components of PB, how and why cells assemble RNP complexes into large foci remain unclear. Using mass spectrometry to analyze proteins immunoisolated with the core PB protein Dhh1, we show that a considerable number of proteins contain low-complexity (LC) sequences, similar to proteins highly represented in mammalian RNP granules. We also show that the Hsp40 chaperone Ydj1, which contains an LC domain and controls prion protein aggregation, is required for the formation of Dhh1-GFP foci upon glucose depletion. New classes of proteins that reproducibly co-enrich with Dhh1-GFP during PB induction include proteins involved in nucleotide or amino acid metabolism, glycolysis, tRNA aminoacylation, and protein folding. Many of these proteins have been shown to form foci in response to other stresses. Finally, analysis of RNA associated with Dhh1-GFP shows enrichment of mRNA encoding the PB protein Pat1 and catalytic RNAs along with their associated mitochondrial RNA-binding proteins, suggesting an active role for RNA in PB function. Thus, global characterization of PB composition has uncovered proteins and RNA that are important for PB assembly.

Download Full-text