Differential toxicity and localization of arginine-rich C9ORF72 dipeptide repeat proteins depend on de-clustering of positive charges
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- Miyagi Tamami
- Department of Pharmacology, Tokyo Medical University
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- Kanekura Kohsuke
- Department of Pharmacology, Tokyo Medical University
Bibliographic Information
- Other Title
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- 筋萎縮性側索硬化症(ALS)原因ジペプチドリピートの細胞内局在および毒性メカニズムの解明
Abstract
<p>Recently, many Amyotrophic lateral sclerosis (ALS)-causing proteins reportedly undergo liquid-liquid phase separation (LLPS). It has also been shown that arginine-rich dipeptide repeat proteins (R-DPRs), poly(PR) and poly(GR), expressed from mutant C9ORF72 are prone to phase separation, and associate with membrane-less organelles formed by LLPS, disturbing their functions. Although R-DPRs share many biochemical features, such as the alternating of Arg, their subcellular localization and toxicity mechanisms are different. However, the mechanisms underlying these differences are unknown. In this study, we analyzed localization, intermolecular interactions, and LLPS of R-DPR variants, and found that these differences are determined by the degree of segregation of Arg charges (Miyagi et al., iScience 2023). In poly(PR), the segregation of arginine side chains by Pro is a critical factor in promoting nucleolar incorporation. In addition, Pro allowed interactions with molecules in a weak but highly multivalent manner. Still, Gly was incapable of separating the Arg well, so poly(GR) showed static localization in the cytosol. Poly(GR) binds to molecules in a strong, but less multivalent manner than poly(PR). These data reveal critical factors that determine biochemical differences in the R-DPRs.</p>
Journal
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- Proceedings for Annual Meeting of The Japanese Pharmacological Society
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Proceedings for Annual Meeting of The Japanese Pharmacological Society 97 (0), 3-B-SS14-1-, 2023
Japanese Pharmacological Society
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Keywords
Details 詳細情報について
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- CRID
- 1390298742739169664
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- ISSN
- 24354953
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- Text Lang
- ja
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- Data Source
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- JaLC
- Crossref
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- Abstract License Flag
- Disallowed