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Brain Proteinopathy 2014
Brain Proteinopathy 2014

開催日 2014/9/11
時間 17:00 - 19:00
会場 Room E(301)
Chairperson(s) 田中 元雅 / Motomasa Tanaka (独立行政法人理化学研究所 脳科学総合研究センター タンパク質構造疾患研究チーム / Laboratory for Protein Conformation Diseases, RIKEN Brain Science Institute, Japan)
貫名 信行 / Nobuyuki Nukina (順天堂大学大学院医学研究科 神経変性疾患病態治療探索講座 / Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Japan)

Reversible Polymeric Fibers Formed From Low-Complexity Sequences as an Underlying Basis of RNA Metabolism and Neurodegenerative Diseases

  • S1-E-3-4
  • Masato Kato:1 Steven McKnight:1 
  • 1:University of Texas Southwestern Medical Centern, USA 

Low-complexity (LC) sequences are disordered regions/domains in proteins with little diversity in their amino acid composition and have been believed to perform important biological roles by unknown mechanisms. We have discovered that purified liquid samples of the LC domains of RNA-binding proteins, such as FUS, hnRNPA2 and TDP-43, made the transition into a gel-like phase in a concentration-dependent manner1,2. The hydrogels are composed of morphologically uniform polymers endowed with an underlying cross-β structure. Unlike pathogenic amyloid fibers, our polymeric fibers are reversible. Hydrogel has capability to capture LC domains of RNA granule proteins via co-polymerization of the LC domain forming the hydrogel and the test LC domain into a single polymeric fiber. The C-terminal domain (CTD) of RNA polymerase II3 and SR domains of splicing factors also bind to the hydrogel, yet these interactions are reversible by phosphorylation of CTD and SR domains by their respective kinases. The outcome of these studies has led to a conceptual framework hypothesizing the structural underpinnings of how dynamic puncta, including RNA granules, transcription factories and nuclear speckles, form in eukaryotic cells. Many mutations in these LC domains found in ALS and FTLD patients have been reported to facilitate fibril aggregate formation of these proteins and thereby to possibly exert toxicity on neuronal cells. We hypothesize, as mechanisms for the aggregate formation, that disease-causing mutations in LC domains tip the equilibrium of reversibility of polymeric fiber formation such that the fibers become unacceptably stable, resulting in accumulation of irreversible polymers.

1. Kato et al., Cell-Free Formation of RNA Granules: Low Complexity Sequence Domains Form Dynamic Fibers Within Hydrogels, Cell 149,753-767 (2012)
2. Han et al., Cell-Free Formation of RNA Granules: Bound RNAs Identify Features and Components of Cellular Assemblies, Cell 149, 768-779 (2012)
3. Kwon et al., Phosphorylation-regulated Binding of RNA Polymerase II to Fibrous Polymers of Low-Complexity Domains, Cell 155, 1049 (2013)

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