Cryo-EM Structure of a Mammalian-specific Alternative Amyloid Exon

Garcia-Pardo, J.; Bartolome-Nafria, A.; Chaves-Sanjuan, A.; Gil-Garcia, M.; Visentin, C.; Bolognesi, M.; Ricagno, S.; Ventura, S.

doi:10.1101/2022.08.24.503855

bioRxiv · 10.1101/2022.08.24.503855

Cryo-EM Structure of a Mammalian-specific Alternative Amyloid Exon

Garcia-Pardo, J.·Bartolome-Nafria, A.·Chaves-Sanjuan, A.·Gil-Garcia, M.·Visentin, C.·Bolognesi, M.·Ricagno, S.·Ventura, S.

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Abstract

hnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing, with missense mutations causing limb-girdle muscular dystrophy-3 (LGMDD3). 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, with the RNA binding domains building a solenoidal coat around them. The amyloid core consists of a single Gly/Tyr-rich and highly hydrophilic filament containing internal water channels. The architecture and activity of hnRNPDL-2 fibrils are reminiscent of functional amyloids, our results suggesting that LGMDD3 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.

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Garcia-Pardo, J., Bartolome-Nafria, A., Chaves-Sanjuan, A., Gil-Garcia, M., Visentin, C., Bolognesi, M., Ricagno, S., Ventura, S.. 2022-08-24. Cryo-EM Structure of a Mammalian-specific Alternative Amyloid Exon. https://doi.org/10.1101/2022.08.24.503855

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