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

Dylan T Murray1,2, Xiaoming Zhou3, Masato Kato3

  • 1Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, MD 20892.

Proceedings of the National Academy of Sciences of the United States of America
|October 4, 2018
PubMed

Insights

Mutations in RNA binding proteins linked to neurological diseases may stem from altered low-complexity (LC) domains. This study reveals these domains form labile polymers, with mutations enhancing stability and disease propensity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Human genetic studies implicate mutations in three related RNA binding proteins in familial neurological diseases.
  • Specific mutations in hnRNPA2, hnRNPA1, and hnRNPDL are linked to multisystem proteinopathy, amyotrophic lateral sclerosis, and limb girdle muscular dystrophy.
  • The affected aspartic acid residues are located in conserved low-complexity (LC) regions, potentially involved in protein disorder or self-association.

Purpose of the Study:

  • To investigate the structural and biophysical properties of the LC domain of hnRNPA2, particularly the D290V mutation.
  • To elucidate the mechanism by which mutations in LC domains contribute to neurological disease pathogenesis.

Main Methods:

  • Solid-state NMR spectroscopy with segmental isotope labeling.
  • Electron microscopy.
  • Biophysical characterization of wild-type and mutant hnRNPA2 LC domains.

Main Results:

  • Both wild-type and D290V mutant hnRNPA2 LC domains form labile polymers with an in-register cross-β conformation.
  • Aspartic acid 290 is charged and immobilized within the polymer core at physiological pH.
  • Polymers formed by the D290V mutant are thermodynamically more stable than wild-type polymers.

Conclusions:

  • The formation of stable polymers by mutated hnRNPA2 LC domains suggests a mechanism for disease pathogenesis.
  • Removal of destabilizing electrostatic interactions at residue 290 may increase the propensity of LC domains to self-associate into disease-associated conformations.
  • These findings provide insights into the molecular basis of neurological disorders linked to RNA binding protein mutations.
Keywords:
cross-beta polymerhnRNPA2low-complexity sequenceneurodegenerative diseasesolid-state NMR

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