7bx7
From Proteopedia
Cryo-EM structure of amyloid fibril formed by hnRNPA1 low complexity domain
Structural highlights
Disease[ROA1_HUMAN] Amyotrophic lateral sclerosis;Inclusion body myopathy with Paget disease of bone and frontotemporal dementia. The disease is caused by mutations affecting the gene represented in this entry.[1] The disease is caused by mutations affecting the gene represented in this entry.[2] Function[ROA1_HUMAN] Involved in the packaging of pre-mRNA into hnRNP particles, transport of poly(A) mRNA from the nucleus to the cytoplasm and may modulate splice site selection. May play a role in HCV RNA replication.[3] Publication Abstract from PubMedHuman 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-beta2 (Kapbeta2), represents the major component of the fibril core. The residues that contribute to the binding of PY-NLS with Kapbeta2 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 Kapbeta2, and highlights the multiple roles of PY-NLS in hnRNPA1 homeostasis. The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure.,Sun Y, Zhao K, Xia W, Feng G, Gu J, Ma Y, Gui X, Zhang X, Fang Y, Sun B, Wang R, Liu C, Li D Nat Commun. 2020 Dec 11;11(1):6349. doi: 10.1038/s41467-020-20227-8. PMID:33311513[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Li, D | Liu, C | Sun, Y P | Zhao, K | Amyloid fibril | Protein fibril
