Structural characterization of the D290V mutation site in hnRNPA2 low-complexity-domain polymers

Dylan T. Murray, Xiaoming Zhou, Masato Kato, Siheng Xiang, Robert Tycko, Steven L. McKnight

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Human genetic studies have given evidence of familial, diseasecausing mutations in the analogous amino acid residue shared by three related RNA binding proteins causative of three neurological diseases. Alteration of aspartic acid residue 290 of hnRNPA2 to valine is believed to predispose patients to multisystem proteinopathy. Mutation of aspartic acid 262 of hnRNPA1 to either valine or asparagine has been linked to either amyotrophic lateral sclerosis or multisystem proteinopathy. Mutation of aspartic acid 378 of hnRNPDL to either asparagine or histidine has been associated with limb girdle muscular dystrophy. All three of these aspartic acid residues map to evolutionarily conserved regions of low-complexity (LC) sequence that may function in states of either intrinsic disorder or labile self-association. Here, we present a combination of solid-state NMR spectroscopy with segmental isotope labeling and electron microscopy on the LC domain of the hnRNPA2 protein. We show that, for both the wild-type protein and the aspartic acid 290-to-valine mutant, labile polymers are formed in which the LC domain associates into an in-register cross-β conformation. Aspartic acid 290 is shown to be charged at physiological pH and immobilized within the polymer core. Polymers of the aspartic acid 290-to-valine mutant are thermodynamically more stable than wild-type polymers. These observations give evidence that removal of destabilizing electrostatic interactions may be responsible for the increased propensity of the mutated LC domains to self-associate in diseasecausing conformations.

Original languageEnglish (US)
Pages (from-to)E9782-E9791
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number42
DOIs
Publication statusPublished - Oct 16 2018

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Keywords

  • Cross-beta polymer
  • HnRNPA2
  • Low-complexity sequence
  • Neurodegenerative disease
  • Solid-state NMR

ASJC Scopus subject areas

  • General

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