Differential Toxicity and Localization of Arginine-rich Dipeptide Repeat Proteins Depend on De-clustering of Positive Charges

Overview

Journal iScience

Publisher Cell Press

Date 2023 Jun 19

PMID 37332605

Authors

Tamami Miyagi

Koji Ueda

Masahiro Sugimoto

Takuya Yagi

Daisuke Ito

Rio Yamazaki

Satoshi Narumi

Yuhei Hayamizu

Hiroshi Uji-I

Masahiko Kuroda

Kohsuke Kanekura

Affiliations

Soon will be listed here.

Abstract

Arginine-rich dipeptide repeat proteins (R-DPRs), poly(PR) and poly(GR), translated from the hexanucleotide repeat expansion in the amyotrophic lateral sclerosis (ALS)-causative gene, contribute significantly to pathogenesis of ALS. Although both R-DPRs share many similarities, there are critical differences in their subcellular localization, phase separation, and toxicity mechanisms. We analyzed localization, protein-protein interactions, and phase separation of R-DPR variants and found that sufficient segregation of arginine charges is necessary for nucleolar distribution. Proline not only efficiently separated the charges, but also allowed for weak, but highly multivalent binding. In contrast, because of its high flexibility, glycine cannot fully separate the charges, and poly(GR) behaves similarly to the contiguous arginines, being trapped in the cytoplasm. We conclude that the amino acid that spaces the arginine charges determines the strength and multivalency of the binding, leading to differences in localization and toxicity mechanisms.

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