Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3
Garcia-Pardo, Javier (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Bartolomé-Nafría, Andrea (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Chaves-Sanjuan, Antonio (Università degli Studi di Milano. Dipartimento di Bioscienze)
Gil Garcia, Marcos (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Visentin, Cristina (Università degli Studi di Milano. Dipartimento di Bioscienze)
Bolognesi, Martino (Università degli Studi di Milano. CRC Fondazione Romeo e Enrica Invernizzi and NOLIMITS)
Ricagno, Stefano (Policlinico San Donato. Institute of Molecular and Translational Cardiology, I.R.C.C.S.)
Ventura, Salvador (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")

Data:	2023
Resum:	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. The authors report the Cryo-EM of hnRNPDL-2 fibrils. The structure highlights features of a functional amyloid associated with limb-girdle muscular dystrophy-3 and explains how alternative splicing controls the assembly of this ribonucleoprotein.
Ajuts:	European Commission 952334 Agencia Estatal de Investigación PID2019-105017RB-I00 Ministerio de Ciencia e Innovación IJC2019-041039-I Ministerio de Educación, Cultura y Deporte FPU16/02465
Nota:	Altres ajuts: ICREA-Acadèmia 2015
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cryoelectron microscopy ; Alternative splicing ; Protein aggregation
Publicat a:	Nature communications, Vol. 14 (January 2023) , art. 239, ISSN 2041-1723

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

12 p, 2.9 MB

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