TDP-43 α-helical structure tunes liquid–liquid phase separation and function

Conicella, Alexander E.; Dignon, Gregory L.; Zerze, Gül H.; Schmidt, Hermann Broder; D’Ordine, Alexandra M.; Kim, Young C.; Rohatgi, Rajat; Ayala, Yuna M.; Mittal, Jeetain; Fawzi, Nicolas L.

doi:10.1073/pnas.1912055117

Title: TDP-43 α-helical structure tunes liquid–liquid phase separation and function

Journal Article · 04 March 2020 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1912055117 · OSTI ID:1603181

Conicella, Alexander E. ^[1]; Dignon, Gregory L. ^[2]; Zerze, Gül H. ^[3]; Schmidt, Hermann Broder ^[4]; D’Ordine, Alexandra M. ^[5]; Kim, Young C. ^[6];

^[7]; Ayala, Yuna M. ^[8]; Mittal, Jeetain ^[9];

^[10]

Brown Univ., Providence, RI (United States). Dept. of Molecular Pharmacology, Physiology, and Biotechnology; Brown Univ., Providence, RI (United States). Graduate Program in Molecular Biology, Cell Biology, and Biochemistry; University of Toronto, Toronto (Canada). Dept. of Chemistry
Lehigh Univ., Bethlehem, PA (United States). Dept. of Chemical and Biomolecular Engineering; Stony Brook Univ., NY (United States). Laufer Center for Physical and Quantitative Biology
Lehigh Univ., Bethlehem, PA (United States). Dept. of Chemical and Biomolecular Engineering; Princeton Univ., NJ (United States). Dept. of Chemical and Biological Engineering
Stanford Univ., CA (United States). School of Medicine, Dept. of Biochemistry
Brown Univ., Providence, RI (United States). Graduate Program in Molecular Biology, Cell Biology, and Biochemistry
Naval Research Lab. (NRL), Washington, DC (United States). Center for Materials Physics and Technology
Stanford Univ., CA (United States). School of Medicine, Dept. of Biochemistry; Stanford Univ., CA (United States). School of Medicine, Dept. of Medicine
Saint Louis Univ., School of Medicine, St. Louis, MO (United States). Edward Doisy Dept. of Biochemistry and Molecular Biology
Lehigh Univ., Bethlehem, PA (United States). Dept. of Chemical and Biomolecular Engineering
Brown Univ., Providence, RI (United States). Dept. of Molecular Pharmacology, Physiology, and Biotechnology

Liquid–liquid phase separation (LLPS) is involved in the formation of membraneless organelles (MLOs) associated with RNA processing. The RNA-binding protein TDP-43 is present in several MLOs, undergoes LLPS, and has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS). While some ALS-associated mutations in TDP-43 disrupt self-interaction and function, here we show that designed single mutations can enhance TDP-43 assembly and function via modulating helical structure. Using molecular simulation and NMR spectroscopy, we observe large structural changes upon dimerization of TDP-43. Two conserved glycine residues (G335 and G338) are potent inhibitors of helical extension and helix–helix interaction, which are removed in part by variants at these positions, including the ALS-associated G335D. Substitution to helix-enhancing alanine at either of these positions dramatically enhances phase separation in vitro and decreases fluidity of phase-separated TDP-43 reporter compartments in cells. Furthermore, G335A increases TDP-43 splicing function in a minigene assay. Therefore, the TDP-43 helical region serves as a short but uniquely tunable module where application of biophysical principles can precisely control assembly and function in cellular and synthetic biology applications of LLPS.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Lehigh Univ., Bethlehem, PA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); USDOE

Grant/Contract Number:: AC02-05CH11231; SC0013979; R01GM118530; 1845734; DP2GM105448; R35GM118082; TG-MCB-120014; DESC0013979

OSTI ID:: 1603181

Alternate ID(s):: OSTI ID: 1625050

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, Issue 11; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 171 works

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