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

• DOI: 10.1073/pnas.1806174115
• Publication Date: 2018-10-02T16:06:29Z
• Authors: Dylan T. Murray; Xiaoming Zhou; Masato Kato; Siheng Xiang; Robert Tycko; Steven L. McKnight
• Keywords: Aspartic acid

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