Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3

Javier Garcia-Pardo, Andrea Bartolomé-Nafría, Antonio Chaves-Sanjuan, Marcos Gil-Garcia, Cristina Visentin, Martino Bolognesi, Stefano Ricagno and Salvador Ventura ()
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Javier Garcia-Pardo: Universitat Autònoma de Barcelona
Andrea Bartolomé-Nafría: Universitat Autònoma de Barcelona
Antonio Chaves-Sanjuan: Università degli Studi di Milano
Marcos Gil-Garcia: Universitat Autònoma de Barcelona
Cristina Visentin: Università degli Studi di Milano
Martino Bolognesi: Università degli Studi di Milano
Stefano Ricagno: Università degli Studi di Milano
Salvador Ventura: Universitat Autònoma de Barcelona

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-35854-0

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