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-Structure paper
タイトル | Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3. |
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ジャーナル・号・ページ | Nat Commun, Vol. 14, Issue 1, Page 239, Year 2023 |
掲載日 | 2023年1月16日 |
著者 | Javier Garcia-Pardo / Andrea Bartolomé-Nafría / Antonio Chaves-Sanjuan / Marcos Gil-Garcia / Cristina Visentin / Martino Bolognesi / Stefano Ricagno / Salvador Ventura / |
PubMed 要旨 | 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 ...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. |
リンク | Nat Commun / PubMed:36646699 / PubMed Central |
手法 | EM (らせん対称) |
解像度 | 2.5 Å |
構造データ | EMDB-14738, PDB-7zir: |
化合物 | ChemComp-HOH: |
由来 |
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キーワード | RNA BINDING PROTEIN / Amyloid / Protein aggregation / Alternative splicing / Exon / Prion-like / LGMD1G / cryoEM structure |