The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure.

Human heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) serves as a key regulating protein in RNA metabolism. Malfunction of hnRNPA1 in nucleo-cytoplasmic transport or dynamic phase separation leads to abnormal amyloid aggregation and neurodegeneration. The low complexity (LC) domain of hnRNPA1 drives both dynamic phase separation and amyloid aggregation. Here, we use cryo-electron microscopy to determine the amyloid fibril structure formed by hnRNPA1 LC domain. Remarkably, the structure reveals that the nuclear localization sequence of hnRNPA1 (termed PY-NLS), which is initially known to mediate the nucleo-cytoplamic transport of hnRNPA1 through binding with karyopherin-β2 (Kapβ2), represents the major component of the fibril core. The residues that contribute to the binding of PY-NLS with Kapβ2 also exert key molecular interactions to stabilize the fibril structure. Notably, hnRNPA1 mutations found in familial amyotrophic lateral sclerosis (ALS) and multisystem proteinopathoy (MSP) are all involved in the fibril core and contribute to fibril stability. Our work illuminates structural understandings of the pathological amyloid aggregation of hnRNPA1 and the amyloid disaggregase activity of Kapβ2, and highlights the multiple roles of PY-NLS in hnRNPA1 homeostasis.

Citation

Yunpeng Sun, Kun Zhao, Wencheng Xia, Guoqin Feng, Jinge Gu, Yeyang Ma, Xinrui Gui, Xia Zhang, Yanshan Fang, Bo Sun, Renxiao Wang, Cong Liu, Dan Li. The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure. Nature communications. 2020 Dec 11;11(1):6349

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PMID: 33311513

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