7ZIR

Cryo-EM structure of hnRNPDL amyloid fibrils

Summary for 7ZIR

• Entry DOI: 10.2210/pdb7zir/pdb
• EMDB information: 14738
• Descriptor: Heterogeneous nuclear ribonucleoprotein D-like (2 entities in total)
• Functional Keywords: amyloid, protein aggregation, alternative splicing, exon, prion-like, lgmd1g, cryoem structure, rna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 229021.33

Authors

Garcia-Pardo, J.,Chaves-Sanjuan, A.,Bartolome-Nafria, A.,Gil-Garcia, M.,Visentin, C.,Bolognesi, M.,Ricagno, S.,Ventura, S. (deposition date: 2022-04-08, release date: 2022-12-28, Last modification date: 2023-12-13)

Primary citation

Garcia-Pardo, J.,Bartolome-Nafria, A.,Chaves-Sanjuan, A.,Gil-Garcia, M.,Visentin, C.,Bolognesi, M.,Ricagno, S.,Ventura, S.
Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3.
Nat Commun, 14:239-239, 2023

PubMed Abstract: hnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing that hosts missense mutations causing limb-girdle muscular dystrophy D3 (LGMD D3). Mammalian-specific alternative splicing (AS) renders three natural isoforms, hnRNPDL-2 being predominant in humans. We present the cryo-electron microscopy structure of full-length hnRNPDL-2 amyloid fibrils, which are stable, non-toxic, and bind nucleic acids. The high-resolution amyloid core consists of a single Gly/Tyr-rich and highly hydrophilic filament containing internal water channels. The RNA binding domains are located as a solenoidal coat around the core. The architecture and activity of hnRNPDL-2 fibrils are reminiscent of functional amyloids, our results suggesting that LGMD D3 might be a loss-of-function disease associated with impaired fibrillation. Strikingly, the fibril core matches exon 6, absent in the soluble hnRNPDL-3 isoform. This provides structural evidence for AS controlling hnRNPDL assembly by precisely including/skipping an amyloid exon, a mechanism that holds the potential to generate functional diversity in RNPs.

PubMed: 36646699
DOI: 10.1038/s41467-023-35854-0

Experimental method

ELECTRON MICROSCOPY (2.5 Å)